Heterocyclic compounds

ABSTRACT

Organic compounds having the structural formulas I, II, and III are provided where the variables have the values described herein and R&lt;1 &gt;and R&lt;2 &gt;in structure I join together to form a 5 to 7 membered substituted or unsubstituted ring including at least one O, N, or S atom, and Z is an O, S, NH or NR group in structures I and II.Pharmaceutical formulations include the organic compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. A method of treating a patient includes administering a pharmaceutical formulation according to the invention to a patient in need thereof.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a divisional of and claims priority to U.S. Ser. No.09/943,382, filed on Aug. 30, 2001, now pending, which claims priorityto U.S. Provisional Application No. 60/231,829 filed on Sep. 1, 2000,and now abandoned, the entire disclosures both of which are incorporatedherein by reference.

FIELD OF THE INVENTION

This invention pertains generally to treating diseases characterized byangiogenesis including cancer. More specifically, the inventiondescribed herein pertains to treating diseases characterized by activityof vascular endothelial growth factor receptor tyrosine kinases. Thepresent invention provides small molecule inhibitors of vascularendothelial growth factor receptor tyrosine kinase, pharmaceuticalformulations containing such inhibitors, methods of treating patientswith such pharmaceutical formulations, and to methods of preparing suchpharmaceutical formulations and inhibitors.

BACKGROUND OF THE INVENTION

Capillaries reach into almost all tissues of the human body and supplytissues with oxygen and nutrients as well as removing waste products.Under typical conditions, the endothelial cells lining the capillariesdo not divide, and capillaries, therefore, do not normally increase innumber or size in a human adult. Under certain normal conditions,however, such as when a tissue is damaged, or during certain parts ofthe menstrual cycle, the capillaries begin to proliferate rapidly. Thisprocess of forming new capillaries from pre-existing blood vessels isknown as angiogenesis or neovascularization. See Folkman, J. ScientificAmerican 275, 150-154 (1996). Angiogenesis during wound healing is anexample of pathophysiological neovascularization during adult life.During wound healing, the additional capillaries provide a supply ofoxygen and nutrients, promote granulation tissue, and aid in wasteremoval. After termination of the healing process, the capillariesnormally regress. Lymboussaki, A. “Vascular Endothelial Growth Factorsand their Receptors in Embryos, Adults, and in Tumors” AcademicDissertation, University of Helsinki, Molecular/Cancer BiologyLaboratory and Department of Pathology, Haartman Institute, (1999).

Angiogenesis also plays an important role in the growth of cancer cells.It is known that once a nest of cancer cells reaches a certain size,roughly 1 to 2 mm in diameter, the cancer cells must develop a bloodsupply in order for the tumor to grow larger as diffusion will not besufficient to supply the cancer cells with enough oxygen and nutrients.Thus, inhibition of angiogenesis is expected to retard or halt thegrowth of cancer cells.

Receptor tyrosine kinases (RTKs) are transmembrane polypeptides thatregulate developmental cell growth and differentiation and remodelingand regeneration of adult tissues. Mustonen, T. et al., J. Cell Biology129, 895-898 (1995); van der Geer, P. et al. Ann Rev. Cell Biol. 10,251-337 (1994). Polypeptide ligands known as growth factors, orcytokines, are known to activate RTKs. Signaling of RTKs involves ligandbinding and a shift in conformation in the external domain of thereceptor resulting in its dimerization. Lymboussaki, A. “VascularEndothelial Growth Factors and their Receptors in Embryos, Adults, andin Tumors” Academic Dissertation, University of Helsinki,Molecular/Cancer Biology Laboratory and Department of Pathology,Haartman Institute, (1999); Ullrich, A. et al., Cell 61, 203-212 (1990).Binding of the ligand to the RTK results in receptortrans-phosphorylation at specific tyrosine residues and subsequentactivation of the catalytic domains for the phosphorylation ofcytoplasmic substrates. Id.

Two subfamilies of RTKs are specific to the vascular endothelium. Theseinclude the vascular endothelial growth factor (VEGF) subfamily and theTie receptor subfamily. Class III RTKs include VEGFR-1, VEGFR-2, andVEGFR-3. Shibuya, M. et al., Oncogene 5, 519-525 (1990); Terman, B. etal., Oncogene 6, 1677-1683 (1991); Aprelikova, O. et al., Cancer Res.52, 746-748 (1992).

Members of the VEGF subfamily have been described as being able toinduce vascular permeability and endothelial cell proliferation andfurther identified as a major inducer of angiogenesis andvasculogenesis. Ferrara, N. et al., Endocrinol. Rev. 18, 4-25 (1997).VEGF is known to specifically bind to RTKs including VEGFR-1 andVEGFR-2. DeVries, C. et al., Science 255, 989-991 (1992); Quinn, T. etal., Proc. Natl. Acad. Sci. 90, 7533-7537 (1993). VEGF stimulates themigration and proliferation of endothelial cells and inducesangiogenesis both in vitro and in vivo. Connolly, D. et al., J. Biol.Chem. 264, 20017-20024 (1989); Connolly, D. et al., J. Clin. Invest. 84,1470-1478 (1989); Ferrara, N. et al., Endocrino. Rew. 18, 4-25 (1997);Leung, D. et al., Science 246, 1306-1309 (1989); Plouet, J. et al., EMBOJ 8, 3801-3806 (1989).

Because angiogenesis is known to be critical to the growth of cancer andto be controlled by VEGF and VEGF-RTK, substantial efforts have beenundertaken to develop therapeutics that are antagonists of VEGF-RTK tothereby inhibit or retard angiogenesis, and hopefully interfere or stoptumor proliferation.

A wide variety of chemical compounds and compositions have been reportedas having activity against one of more the VEGF-RTKs. Examples includequinoline derivatives such as described in WO 98/13350,aminonicotinamide derivatives (see, e.g., WO 01/55114), antisensecompounds (see, e.g., WO 01/52904), peptidomimetics (see, e.g., WO01/52875), quinazoline derivatives (see, e.g., U.S. Pat. No. 6,258,951)monoclonal antibodies (see, e.g., EP 1 086 705 A1), various5,10,15,20-tetraaryl-porphyrins and 5,10,15-triaryl-corroles (see, e.g.,WO 00/27379), heterocyclic alkanesulfonic and alkane carboxylic acidderivatives (see, e.g., DE19841985), oxindolylquinazoline derivatives(see, e.g., WO 99/10349), 1,4-diazaanthracine derivatives (see, e.g.,U.S. Pat. No. 5,763,441), and cinnoline derivatives (see, e.g., WO97/34876), and various indazole compounds (see e.g., WO 01/02369 and WO01/02369).

Various indolyl-substituted compounds have recently been disclosed in WO01/29025, and various benzimidazolyl compounds have recently beendisclosed in WO 01/28993. These compounds are reportedly capable ofinhibiting, modulating, and/or regulating signal transduction of bothreceptor-type and non-receptor tyrosine kinases. Some of the disclosedcompounds contain a quinolone fragment bonded to the indolyl orbenzimidazolyl group.

The synthesis of 4-hydroxy quinolone and 4-hydroxy quinoline derivativesis disclosed in a number of references. For example, Ukrainets et al.have disclosed the synthesis of3-(Benzimidazol-2-yl)-4-hydroxy-2-oxo-1,2-dihydroquinoline. Ukrainets,I. et al., Tet. Lett. 42, 7747-7748 (1995); Ukrainets, I. et al.,Khimiya Geterotsiklicheskikh Soedinii, 2, 239-241(1992). Ukrainets hasalso disclosed the synthesis, anticonvulsive and antithyroid activity ofother 4-hydroxy quinolones and thio analogs such as1H-2-oxo-3-(2-benzimidazolyl)-4-hyrdoxyquinoline. Ukrainets, I. et al.,Khimiya Geterotsiklicheskikh Soedinii, 1, 105-108 (1993); Ukrainets, I.et al., Khimiya Geterotsiklicheskikh Soedinii, 8, 1105-1108 (1993);Ukrainets, I. et al., Chem. Heterocyclic Comp. 33, 600-604, (1997).

The synthesis of various quinoline derivatives is disclosed in WO97/48694. These compounds are disclosed as capable of binding to nuclearhormone receptors and being useful for stimulating osteoblastproliferation and bone growth. The compounds are also disclosed as beinguseful in the treatment or prevention of diseases associated withnuclear hormone receptor families.

Various quinoline derivatives in which the benzene ring of the quinoloneis substituted with a sulfur group are disclosed in WO 92/18483. Thesecompounds are disclosed as being useful in pharmaceutical formulationsand as medicaments.

Quinolone and coumarin derivatives have been disclosed as having use ina variety of applications unrelated to medicine and pharmaceuticalformulations. References that describe the preparation of quinolonederivatives for use in photopolymerizable compositions or forluminescent properties include: U.S. Pat. No. 5,801,212 issued toOkamoto et al.; JP 8-29973; JP 7-43896; JP 6-9952; JP 63-258903; EP797376; and DE 23 63 459.

Despite the exploration of a variety of chemistries to provideVEGF-RTK-antagonist therapies, a continuing need exists for compoundsthat inhibit the proliferation of capillaries, inhibit the growth oftumors, and/or inhibit vascular endothelial growth factor receptortyrosine kinase and pharmaceutical formulations that contain suchcompounds. A need also exists for methods for administering suchcompounds and pharmaceutical formulations to patients in need thereof.

SUMMARY OF THE INVENTION

The present invention provides compounds, pharmaceutical formulationsincluding the compounds, methods of preparing the pharmaceuticalformulations, and methods of treating patients with the pharmaceuticalformulations and compounds.

The present invention provides compounds having the structure I. Theinvention also provides tautomers of the compounds, pharmaceuticallyacceptable salts of the compounds, and pharmaceutically acceptable saltsof the tautomers. Structure I has the following formula:

where:

Y is selected from —OH, —OR⁸ groups, —SH, —SR⁹ groups, —NR¹⁰R¹¹ groups,—CN, —C(═O)—R¹² groups, substituted or unsubstituted alkyl groups,substituted or unsubstituted alkenyl groups, substituted orunsubstituted alkynyl groups, substituted or unsubstituted aralkylgroups, substituted or unsubstituted heterocyclylalkyl groups,substituted or unsubstituted alkylaminoalkyl groups, substituted orunsubstituted dialkylaminoalkyl groups, substituted or unsubstitutedarylaminoalkyl groups, substituted or unsubstituted diarylaminoalkylgroups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups,substituted or unsubstituted heterocyclylaminoalkyl groups, substitutedand unsubstituted diheterocyclylaminoalkyl groups, substituted andunsubstituted (alkyl)(heterocyclyl)aminoalkyl groups, substituted andunsubstituted (aryl)(heterocyclyl)aminoalkyl groups, substituted orunsubstituted heterocyclyl groups, substituted or unsubstituted arylgroups, substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups;

Z is O, S, or a NR¹³ group;

R¹ and R² join to form a 5 to 7 membered substituted or unsubstitutedring including at least one O, N, or S atom;

R³ and R¹³ may be the same or different and are selected from H, —OH,substituted or unsubstituted alkoxy groups, substituted or unsubstitutedaryloxy groups, —NH₂, substituted or unsubstituted alkylamino groups,substituted or unsubstituted arylamino groups, substituted orunsubstituted dialkylamino groups, substituted or unsubstituteddiarylamino groups, substituted or unsubstituted (alkyl)(aryl)aminogroups, substituted and unsubstituted heterocyclylamino groups,substituted and unsubstituted diheterocyclylamino groups, substitutedand unsubstituted (alkyl)(heterocyclyl)amino groups, substituted andunsubstituted (aryl)(heterocyclyl)amino groups, substituted andunsubstituted heterocylyloxy groups, substituted or unsubstituted alkylgroups, substituted or unsubstituted aryl groups, —C(═O)H, —C(═O)-alkylgroups, or —C(═O)-aryl groups;

R⁴, R⁵, R⁶, and R⁷ may be the same or different and are independentlyselected from H, Cl, Br, F, I, —NO₂, —CN, —OH, —OR¹⁴ groups, —NR¹⁵R¹⁶groups, —C(═O)R¹⁷ groups, 13 SH, —SR¹⁸ groups, —S(═O)R¹⁹ groups,S(═O)₂R²⁰ groups, substituted or unsubstituted amidinyl groups,substituted or unsubstituted guanidinyl groups, substituted orunsubstituted primary, secondary, or tertiary alkyl groups, substitutedor unsubstituted aryl groups, substituted or unsubstituted alkenylgroups, substituted or unsubstituted alkynyl groups, substituted orunsubstituted heterocyclyl groups, substituted or unsubstitutedalkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkylgroups, substituted or unsubstituted arylaminoalkyl groups, substitutedor unsubstituted diarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(alkyl)(heterocyclyl)aminoalkyl groups, substituted and unsubstituted(aryl)(heterocyclyl)aminoalkyl groups, substituted or unsubstitutedheterocyclylalkyl groups, substituted or unsubstituted aminoalkylgroups, substituted or unsubstituted heterocyclylaminoalkyl groups,substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups;

R⁸ is selected from substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, substituted or unsubstitutedheterocyclyl groups, substituted or unsubstituted heterocyclylalkylgroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkylgroups, —C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,—C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —NH₂, —NH(alkyl) groups, —NH(aryl) groups,—N(alkyl)₂ groups, —N(alkyl)(aryl) groups, —N(aryl)₂ groups,—C(═O)NH(heterocyclyl) groups, —C(═O)N(heterocyclyl)₂ groups,—C(═O)N(alkyl)(heterocyclyl) groups, or —C(═O)N(aryl)(heterocyclyl)groups;

R⁹ and R¹⁸ may be the same or different and are independently selectedfrom substituted or unsubstituted alkyl groups, or substituted orunsubstituted aryl groups;

R¹⁰ is selected from H, substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, or substituted orunsubstituted heterocyclyl groups;

R¹¹ is selected from H, substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, substituted or unsubstitutedheterocyclyl groups, —OH, alkoxy groups, aryloxy groups, —NH₂,substituted or unsubstituted heterocyclylalkyl groups, substituted orunsubstituted aminoalkyl groups, substituted or unsubstitutedalkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkylgroups, substituted or unsubstituted arylaminoalkyl groups, substitutedor unsubstituted diarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkylaminogroups, substituted or unsubstituted arylamino groups, substituted orunsubstituted dialkylamino groups, substituted or unsubstituteddiarylamino groups, substituted or unsubstituted (alkyl)(aryl)aminogroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkylgroups, —C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,—C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —C(═O)-heterocyclyl groups,—C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,—C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups,—C(═O)—N(aryl)(heterocyclyl) groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(alkyl)(heterocyclyl)aminoalkyl groups, substituted and unsubstituted(aryl)(heterocyclyl)aminoalkyl groups, substituted or unsubstitutedhydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups,substituted or unsubstituted aryloxyalkyl groups, or substituted orunsubstituted heterocyclyloxyalkyl groups;

R¹² is selected from H, —OH, alkoxy groups, aryloxy groups, —NH₂,—NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂ groups, —N(aryl)₂groups, —N(alkyl)(aryl) groups, substituted or unsubstituted alkylgroups, substituted or unsubstituted aryl groups, —NH(heterocyclyl)groups, —N(heterocyclyl)₂ groups, —N(alkyl)(heterocyclyl) groups, or—N(aryl)(heterocyclyl) groups;

R¹⁴ is selected from substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, substituted or unsubstitutedheterocyclyl groups, substituted or unsubstituted heterocyclylalkylgroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups,—C(═O)-heterocyclyl groups,—C(═O)NH₂, —C(═O)NH(alkyl) groups,—C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —C(═O)NH-heterocyclyl groups,—C(═O)N-(heterocyclyl)₂ groups, —C(═O)N(alkyl)(heterocyclyl) groups,—C(═O)N(aryl)(heterocyclyl) groups, substituted or unsubstitutedaminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups,substituted or unsubstituted dialkylaminoalkyl groups, substituted orunsubstituted arylaminoalkyl groups, substituted or unsubstituteddiarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted or unsubstituteddiheterocyclylaminoalkyl groups, substituted or unsubstituted(heterocyclyl)(alkyl)aminoalkyl groups, substituted or unsubstituted(heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstitutedalkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups,substituted or unsubstituted hydroxyalkyl groups, or substituted orunsubstituted heterocyclyloxyalkyl groups;

R¹⁵ is selected from H, substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, or substituted orunsubstituted heterocyclyl groups;

R¹⁶ is selected from H, substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, substituted or unsubstitutedheterocyclyl groups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups,—C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups,—C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl)groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups, substituted orunsubstituted aminoalkyl groups, substituted or unsubstitutedalkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkylgroups, substituted or unsubstituted arylaminoalkyl groups, substitutedor unsubstituted diarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstitutedheterocyclylalkyl groups, —C(═O)-heterocyclyl groups,—C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,—C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups,—C(═O)—N(aryl)(heterocyclyl) groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(heterocyclyl)(alkyl)aminoalkyl groups, substituted and unsubstituted(heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstitutedhydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups,substituted or unsubstituted aryloxyalkyl groups, or substituted orunsubstituted heterocyclyloxyalkyl groups; and

R¹⁷, R¹⁹, and R²⁰ may be the same or different and are independentlyselected from H, —NH₂, —NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂groups, —N(aryl)₂ groups, —N(alkyl)(aryl) groups, —NH(heterocyclyl)groups, —N(heterocyclyl)(alkyl) groups, —N(heterocyclyl)(aryl) groups,—N(heterocyclyl)₂ groups, substituted and unsubstituted alkyl groups,substituted and unsubstituted aryl groups, —OH, substituted andunsubstituted alkoxy groups, substituted and unsubstituted heterocyclylgroups, substituted and unsubstituted aryloxy groups, heterocyclyloxygroups, —NHOH, —N(alkyl)OH groups, —N(aryl)OH groups, —N(alkyl)O-alkylgroups, —N(aryl)O-alkyl groups, —N(alkyl)O-aryl groups, and—N(aryl)O-aryl groups.

Preferred compounds having the structure I are provided where Y isselected from —OH, —OR⁸ groups, or —NR¹⁰R¹¹ groups, or more preferablyis a —NR¹⁰R¹¹ group.

Still other preferred compounds having the structure I are provided inwhich Z is an NR¹³ group and the rest of the compound is consistent withany of the above-described compounds.

In still other preferred compounds of structure I, R⁴ and R⁷ arehydrogen, R⁶ and R⁷ are selected from hydrogen or an alkyl group havingfrom 1 to 4 carbon atoms, and the rest of the compound is consistentwith any of the above-described compounds.

Still other compounds having the formula of structure I are provided inwhich R⁵ or R⁶ is an —OR¹⁴ group and R¹⁴ is an alkyl, aryl,heterocyclyl, or heterocyclylalkyl group and the rest of the molecule isconsistent with any of the above-described compounds.

In still further preferred compounds having the formula of structure I,R⁵ or R⁶ is a —OCH₂(CH₂)_(q)(heterocyclyl) group where q is 0, 1, 2, 3,or 4 and the rest of the compound is consistent with any of theabove-described compounds.

Other preferred compounds having the structure I are provided in whichR¹⁷ is selected from substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, —NH₂, —NH(alkyl) groups,—N(alkyl)₂ groups, —NH(aryl) groups, —N(aryl)₂ groups, —N(alkyl)(aryl)groups, —NH(heterocyclyl) groups, —N(heterocyclyl)(alkyl) groups,—N(heterocyclyl)(aryl) groups, —N(heterocyclyl)₂ groups, or N-containingheterocycles, and the N-containing heterocycles are bonded to thecarbonyl carbon of the —C(═O)—R¹⁷ group through either a nitrogen atomor a carbon atom in the rings of the N-containing heterocycles.

The present invention also provides compounds having the structure III.The invention also provides tautomers of the compounds, pharmaceuticallyacceptable salts of the compounds, and pharmaceutically acceptable saltsof the tautomers. Structure III has the following formula:

where:

W¹, W², W³, and W⁴ are selected from C or N, and at least one of W¹, W²,W³, or W⁴ is N;

X¹, X², X³, and X⁴ are selected from C or N, and at least one of X¹, X²,X³, or X⁴ is N;

Y is selected from H, —OH, —OR¹⁰ groups, —SH, —SR¹¹ groups, —NR¹²R¹³groups, —CN, —C(═O)—R¹⁴ groups, substituted or unsubstituted alkylgroups, substituted or unsubstituted alkenyl groups, substituted orunsubstituted alkynyl groups, substituted or unsubstituted aralkylgroups, substituted or unsubstituted heterocyclylalkyl groups,substituted or unsubstituted alkylaminoalkyl groups, substituted orunsubstituted dialkylaminoalkyl groups, substituted or unsubstitutedarylaminoalkyl groups, substituted or unsubstituted diarylaminoalkylgroups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups,substituted or unsubstituted heterocyclylaminoalkyl groups, substitutedand unsubstituted diheterocyclylaminoalkyl groups, substituted andunsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted andunsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted orunsubstituted heterocyclyl groups, substituted or unsubstituted arylgroups, substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups;

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ may be the same or different and areindependently selected from H, Cl, Br, F, I, —NO₂, —CN, —OH, —OR¹⁵groups, —NR¹⁶R¹⁷ groups, —C(═O)R¹⁸ groups, —SH, —SR¹⁹ groups, —S(═O)R²⁰groups, S(═O)₂R¹⁹ groups, substituted or unsubstituted amidinyl groups,substituted or unsubstituted guanidinyl groups, substituted orunsubstituted primary, secondary, or tertiary alkyl groups, substitutedor unsubstituted aryl groups, substituted or unsubstituted alkenylgroups, substituted or unsubstituted alkynyl groups, substituted orunsubstituted heterocyclyl groups, substituted or unsubstitutedalkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkylgroups, substituted or unsubstituted arylaminoalkyl groups, substitutedor unsubstituted diarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstitutedheterocyclylalkyl groups, substituted or unsubstituted aminoalkylgroups, substituted or unsubstituted heterocyclylaminoalkyl groups,substituted and unsubstituted diheterocyclylaminoalkyl groups,substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups,substituted and unsubstituted (aryl)(heterocyclyl)aminoalkyl groups,substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups, and R¹ is absent or H if W¹ is N, R² isabsent or H if W² is N, R³ is absent or H if W³ is N, R⁴ is absent or Hif W⁴ is N, R⁵ is absent or H if X¹ is N, R⁶ is absent or H if X² is N,R⁷ is absent or H if X³ is N, and R⁸ is absent or H if X⁴ is N;

R⁹ is selected from H, —OH, substituted or unsubstituted alkoxy groups,substituted or unsubstituted aryloxy groups, —NH₂, substituted orunsubstituted alkylamino groups, substituted or unsubstituted arylaminogroups, substituted or unsubstituted dialkylamino groups, substituted orunsubstituted diarylamino groups, substituted or unsubstituted(alkyl)(aryl)amino groups, substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, —C(═O)H, —C(═O)-alkyl groups,or —C(═O)-aryl groups;

R¹⁰ is selected from substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, substituted or unsubstitutedheterocyclyl groups, substituted or unsubstituted heterocyclylalkylgroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkylgroups, —C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,—C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —NH₂, —NH(alkyl) groups, —NH(aryl) groups,—N(alkyl)₂ groups, —N(alkyl)(aryl) groups, —N(aryl)₂ groups,—C(═O)NH(heterocyclyl) groups, —C(═O)N(heterocyclyl)₂ groups,—C(═O)N(alkyl)(heterocyclyl) groups, or —C(═O)N(aryl)(heterocyclyl)groups;

R¹⁰ and R¹⁹ may be the same or different and are independently selectedfrom substituted or unsubstituted alkyl groups, or substituted orunsubstituted aryl groups;

R¹² is selected from H, substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, or substituted orunsubstituted heterocyclyl groups;

R¹³ is selected from H, substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, substituted or unsubstitutedheterocyclyl groups, —OH, alkoxy groups, aryloxy groups, —NH₂,substituted or unsubstituted heterocyclylalkyl groups, substituted orunsubstituted aminoalkyl groups, substituted or unsubstitutedalkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkylgroups, substituted or unsubstituted arylaminoalkyl groups, substitutedor unsubstituted diarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkylaminogroups, substituted or unsubstituted arylamino groups, substituted orunsubstituted dialkylamino groups, substituted or unsubstituteddiarylamino groups, substituted or unsubstituted (alkyl)(aryl)aminogroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkylgroups, —C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,—C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —C(═O)-heterocyclyl groups,—C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,—C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups,—C(═O)—N(aryl)(heterocyclyl) groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkylgroups, substituted or unsubstituted alkoxyalkyl groups, substituted orunsubstituted aryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups;

R¹⁴ is selected from H, —OH, alkoxy groups, aryloxy groups, —NH₂,—NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂ groups, —N(aryl)₂groups, —N(alkyl)(aryl) groups, substituted or unsubstituted alkylgroups, substituted or unsubstituted aryl groups, —NH(heterocyclyl)groups, —N(heterocyclyl)₂ groups, —N(alkyl)(heterocyclyl) groups, or—N(aryl)(heterocyclyl) groups;

R¹⁵ is selected from substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, substituted or unsubstitutedheterocyclyl groups, substituted or unsubstituted heterocyclylalkylgroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups,—(C═O)-heterocyclyl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,—C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —C(═O)NH-heterocyclyl groups,—C(═O)N-(heterocyclyl)₂ groups, —C(═O)N(alkyl)(heterocyclyl) groups,—C(═O)N(aryl)(heterocyclyl) groups, substituted or unsubstitutedaminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups,substituted or unsubstituted dialkylaminoalkyl groups, substituted orunsubstituted arylaminoalkyl groups, substituted or unsubstituteddiarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted or unsubstituteddiheterocyclylaminoalkyl groups, substituted or unsubstituted(heterocyclyl)(alkyl)aminoalkyl groups, substituted or unsubstituted(heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstitutedalkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups,substituted or unsubstituted hydroxyalkyl groups, or substituted orunsubstituted heterocyclyloxyalkyl groups;

R¹⁶ is selected from H, substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, or substituted orunsubstituted heterocyclyl groups;

R¹⁷ is selected from H, substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, substituted or unsubstitutedheterocyclyl groups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups,—C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups,—C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl)groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups, substituted orunsubstituted aminoalkyl groups, substituted or unsubstitutedalkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkylgroups, substituted or unsubstituted arylaminoalkyl groups, substitutedor unsubstituted diarylaminoalkyl groups, substituted or unsubstituted(aryl)(alkyl)aminoalkyl groups, substituted or unsubstitutedheterocyclylalkyl groups, —C(═O)-heterocyclyl groups,—C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,—C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups,—C(═O)—N(aryl)(heterocyclyl) groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(heterocyclyl)(alkyl)aminoalkyl groups, substituted and unsubstituted(heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstitutedhydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups,substituted or unsubstituted aryloxyalkyl groups, or substituted orunsubstituted heterocyclyloxyalkyl groups; and

R¹⁸, R²⁰, and R²¹ may be the same or different and are independentlyselected from H, —NH₂, —NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂groups, —N(aryl)₂ groups, —N(alkyl)(aryl) groups, —NH(heterocyclyl)groups, —N(heterocyclyl)(alkyl) groups, —N(heterocyclyl)(aryl) groups,—N(heterocyclyl)₂ groups, substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, —OH, substituted orunsubstituted alkoxy groups, substituted or unsubstituted heterocyclylgroups, substituted or unsubstituted aryloxy groups, heterocyclyloxygroups, —NHOH, —N(alkyl)OH groups, —N(aryl)OH groups, —N(alkyl)O-alkylgroups, —N(aryl)O-alkyl groups, —N(alkyl)O-aryl groups, and—N(aryl)O-aryl groups.

Preferred compounds having structure III are also provided where one ofW¹, W², W³, or W⁴ is N.

Preferred compounds having structure III are also provided where one ofX¹, X², X³, or X⁴ is N.

Preferred compounds having structure III are also provided where Y isselected from H, —OH, —OR¹⁰ groups, or —NR¹²R¹³ groups, or morepreferably is a —NR¹²R¹³ group.

Still other preferred compounds having structure III are provided whereR⁵ is H, X⁴ is N, R⁶ and R⁷ are selected from H or alkyl groups havingfrom one to four carbon atoms, and the rest of the compound isconsistent with any of the above-described compounds.

Still other compounds of structure III are provided in which R⁶ or R⁷ isan —OR¹⁵ group and R¹⁵ is an alkyl, aryl, heterocyclyl, orheterocyclylalkyl group and the rest of the molecule is consistent withany of the above-described compounds.

In still further preferred compounds of structure III, R⁶ or R⁷ is a—OCH₂(CH₂)_(q)(heterocyclyl) group, q is 0, 1, 2, 3, or 4, and the restof the compound is consistent with any of the above-described compounds.

Other preferred compounds having the structure III are provided in whichR¹⁸ is selected from substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, —NH₂, —NH(alkyl) groups,—N(alkyl)₂ groups, —NH(aryl) groups, —N(aryl)₂ groups, —N(alkyl)(aryl)groups, —NH(heterocyclyl) groups, —N(heterocyclyl)(alkyl) groups,—N(heterocyclyl)(aryl) groups, —N(heterocyclyl)₂ groups, or N-containingheterocycles, and the N-containing heterocycles are bonded to thecarbonyl carbon of the —C(═O)—R¹⁸ group through either a nitrogen atomor a carbon atom in the rings of the N-containing heterocycles.

Pharmaceutical formulations according to the present invention areprovided which include any of the compounds described above incombination with a pharmaceutically acceptable carrier.

A method of treating a patient in need of an inhibitor of vascularendothelial growth factor receptor tyrosine kinase is provided whichincludes administering an effective amount of the pharmaceuticalformulation according to the present invention to a patient in needthereof.

Further objects, features and advantages of the invention will beapparent from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel compounds that act as antagonistsof receptor tyrosine kinases, and, more particularly, as inhibitors ofbFGF and VEGF-RTK function. The compounds provided herein can beformulated into pharmaceutical formulations that are useful in treatingpatients with a need for an inhibitor of VEGF-RTK, especially, inparticular embodiments, to provide compositions and methods for reducingcapillary proliferation and in the treatment of cancer.

The following abbreviations and definitions are used throughout thisapplication:

“VEGF” is an abbreviation that stands for vascular endothelial growthfactor.

“RTK” is an abbreviation that stands for receptor tyrosine kinase.

“VEGF-RTK” is an abbreviation that stands for vascular endothelialgrowth factor receptor tyrosine kinase.

“Flt-1” is an abbreviation that stands for fins-like tyrosine kinase-1,also known as vascular endothelial growth factor receptor-1 or “VEGFR1”.

“KDR” is an abbreviation that stands for kinase-insert domain tyrosinekinase, also known as vascular endothelial growth factor receptor-2 or“VEGFR2”.

“bFGF” is an abbreviation that stands for basic fibroblast growthfactor.

“bFGFR” is an abbreviation that stands for basic fibroblast growthfactor receptor.

Generally, reference to a certain element such as hydrogen or H is meantto include all isotopes of that element. For example, if an R group isdefined to include hydrogen or H, it also includes deuterium andtritium.

The phrase “unsubstituted alkyl” refers to alkyl groups that do notcontain heteroatoms. Thus the phrase includes straight chain alkylgroups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,octyl, nonyl, decyl, undecyl, dodecyl and the like. The phrase alsoincludes branched chain isomers of straight chain alkyl groups,including but not limited to, the following which are provided by way ofexample: —CH(CH₃)₂, —CH(CH₃)(CH₂CH₃), —CH(CH₂CH₃)₂, —C(CH₃)₃,—C(CH₂CH₃)₃, —CH₂CH(CH₃)₂, —CH₂CH(CH₃)(CH₂CH₃), —CH₂CH(CH₂CH₃)₂,—CH₂C(CH₃)₃, —CH₂C(CH₂CH₃)₃, —CH(CH₃)CH(CH₃)(CH₂CH₃), —CH₂CH₂CH(CH₃)₂,—CH₂CH₂CH(CH₃)(CH₂CH₃), —CH₂CH₂CH(CH₂CH₃)₂, —CH₂CH₂C(CH₃)₃,—CH₂CH₂C(CH₂CH₃)₃, —CH(CH₃)CH₂CH(CH₃)₂, —CH(CH₃)CH(CH₃)CH(CH₃)₂,—CH(CH₂CH₃)CH(CH₃)CH(CH₃)(CH₂CH₃), and others. The phrase also includescyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted withstraight and branched chain alkyl groups as defined above. The phrasealso includes polycyclic alkyl groups such as, but not limited to,adamantyl and norbornyl and such rings substituted with straight andbranched chain alkyl groups as defined above. Thus the phraseunsubstituted alkyl groups includes primary alkyl groups, secondaryalkyl groups, and tertiary alkyl groups. Unsubstituted alkyl groups maybe bonded to one or more carbon atom(s), oxygen atom(s), nitrogenatom(s), and/or sulfur atom(s) in the parent compound. Preferredunsubstituted alkyl groups include straight and branched chain alkylgroups and cyclic alkyl groups having 1 to 20 carbon atoms. Morepreferred such unsubstituted alkyl groups have from 1 to 10 carbon atomswhile even more preferred such groups have from 1 to 5 carbon atoms.Most preferred unsubstituted alkyl groups include straight and branchedchain alkyl groups having from 1 to 3 carbon atoms and include methyl,ethyl, propyl, and —CH(CH₃)₂.

The phrase “substituted alkyl” refers to an unsubstituted alkyl group asdefined above in which one or more bonds to a carbon(s) or hydrogen(s)are replaced by a bond to non-hydrogen and non-carbon atoms such as, butnot limited to, a halogen atom in halides such as F, Cl, Br, and I; andoxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxygroups, and ester groups; a sulfur atom in groups such as thiol groups,alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups, andsulfoxide groups; a nitrogen atom in groups such as amines, amides,alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines,N-oxides, imides, and enamines; a silicon atom in groups such as intrialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups,and triarylsilyl groups; and other heteroatoms in various other groups.Substituted alkyl groups also include groups in which one or more bondsto a carbon(s) or hydrogen(s) atom is replaced by a bond to a heteroatomsuch as oxygen in carbonyl, carboxyl, and ester groups; nitrogen ingroups such as imines, oximes, hydrazones, and nitriles. Substitutedalkyl groups include, among others, alkyl groups in which one or morebonds to a carbon or hydrogen atom is/are replaced by one or more bondsto fluorine atoms. One Example of a substituted alkyl group is thetrifluoromethyl group and other alkyl groups that contain thetrifluoromethyl group. Other alkyl groups include those in which one ormore bonds to a carbon or hydrogen atom is replaced by a bond to anoxygen atom such that the substituted alkyl group contains a hydroxyl,alkoxy, aryloxy, or heterocyclyloxy group. Still other substituted alkylgroups include alkyl groups that have an amine, alkylamine,dialkylamine, arylamine, (alkyl)(aryl)amine,diarylamine,heterocyclylamine, (alkyl)(heterocyclyl)amine,(aryl)(heterocyclyl)amine, or diheterocyclylamine group.

The phrase “unsubstituted aryl” refers to aryl groups that do notcontain heteroatoms. Thus the phrase includes, but is not limited to,groups such as phenyl, biphenyl, anthracenyl, naphthenyl by way ofexample. Although the phrase “unsubstituted aryl” includes groupscontaining condensed rings such as naphthalene, it does not include arylgroups that have other groups such as alkyl or halo groups bonded to oneof the ring members, as aryl groups such as tolyl are considered hereinto be substituted aryl groups as described below. A preferredunsubstituted aryl group is phenyl. Unsubstituted aryl groups may bebonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s),and/or sulfur atom(s) in the parent compound, however.

The phrase “substituted aryl group” has the same meaning with respect tounsubstituted aryl groups that substituted alkyl groups had with respectto unsubstituted alkyl groups. However, a substituted aryl group alsoincludes aryl groups in which one of the aromatic carbons is bonded toone of the non-carbon or non-hydrogen atoms described above and alsoincludes aryl groups in which one or more aromatic carbons of the arylgroup is bonded to a substituted and/or unsubstituted alkyl group. Thus,the phrase “substituted aryl” includes, but is not limited to tolyl, andhydroxyphenyl among others.

The phrase “unsubstituted alkenyl” refers to straight and branched chainand cyclic groups such as those described with respect to unsubstitutedalkyl groups as defined above, except that at least one double bondexists between two carbon atoms. Examples include, but are not limitedto vinyl, —CH═C(H)(CH₃), —CH═C(CH₃)₂, —C(CH₃)═C(H)₂, —C(CH₃)═C(H)(CH₃),—C(CH₂CH₃)═CH₂, cyclohexenyl, cyclopentenyl, cyclohexadienyl,butadienyl, pentadienyl, and hexadienyl among others.

The phrase “substituted alkenyl” has the same meaning with respect tounsubstituted alkenyl groups that substituted alkyl groups had withrespect to unsubstituted alkyl groups. A substituted alkenyl groupincludes alkenyl groups in which a non-carbon or non-hydrogen atom isbonded to a carbon double bonded to another carbon and those in whichone of the non-carbon or non-hydrogen atoms is bonded to a carbon notinvolved in a double bond to another carbon.

The phrase “unsubstituted alkynyl” refers to straight and branched chaingroups such as those described with respect to unsubstituted alkylgroups as defined above, except that at least one triple bond existsbetween two carbon atoms. Examples include, but are not limited to—C≡C(H), —C≡C(CH₃), —C≡C(CH₂CH₃), —C(H₂)C≡C(H), —C(H)₂C≡C(CH₃), and—C(H)₂C≡C(CH₂CH₃) among others.

The phrase “substituted alkynyl” has the same meaning with respect tounsubstituted alkynyl groups that substituted alkyl groups had withrespect to unsubstituted alkyl groups. A substituted alkynyl groupincludes alkynyl groups in which a non-carbon or non-hydrogen atom isbonded to a carbon triple bonded to another carbon and those in which anon-carbon or non-hydrogen atom is bonded to a carbon not involved in atriple bond to another carbon.

The phrase “unsubstituted aralkyl” refers to unsubstituted alkyl groupsas defined above in which a hydrogen or carbon bond of the unsubstitutedalkyl group is replaced with a bond to an aryl group as defined above.For example, methyl (—CH₃) is an unsubstituted alkyl group. If ahydrogen atom of the methyl group is replaced by a bond to a phenylgroup, such as if the carbon of the methyl were bonded to a carbon ofbenzene, then the compound is an unsubstituted aralkyl group (i.e. abenzyl group). Thus the phrase includes, but is not limited to, groupssuch as benzyl, diphenylmethyl, and 1-phenylethyl (—CH(C₆H₅)(CH₃)) amongothers.

The phrase “substituted aralkyl” has the same meaning with respect tounsubstituted aralkyl groups that substituted aryl groups had withrespect to unsubstituted aryl groups. However, a substituted aralkylgroup also includes groups in which a carbon or hydrogen bond of thealkyl part of the group is replaced by a bond to a non-carbon or anon-hydrogen atom. Examples of substituted aralkyl groups include, butare not limited to, —CH₂C(═O)(C₆H₅), and —CH₂(2-methylphenyl) amongothers.

The phrase “unsubstituted heterocyclyl” refers to both aromatic andnonaromatic ring compounds including monocyclic, bicyclic, andpolycyclic ring compounds such as, but not limited to, quinuclidyl,containing 3 or more ring members of which one or more is a heteroatomsuch as, but not limited to, N, O, and S. Although the phrase“unsubstituted heterocyclyl” includes condensed heterocyclic rings suchas benzimidazolyl, it does not include heterocyclyl groups that haveother groups such as alkyl or halo groups bonded to one of the ringmembers as compounds such as 2-methylbenzimidazolyl are substitutedheterocyclyl groups. Examples of heterocyclyl groups include, but arenot limited to: unsaturated 3 to 8 membered rings containing 1 to 4nitrogen atoms such as, but not limited to pyrrolyl, pyrrolinyl,imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl,pyridazinyl, triazolyl (e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,2H-1,2,3-triazolyl etc.), tetrazolyl, (e.g. 1H-tetrazolyl,2H-tetrazolyl, etc.); saturated 3 to 8 membered rings containing 1 to 4nitrogen atoms such as, but not limited to, pyrrolidinyl,imidazolidinyl, piperidinyl, piperazinyl; condensed unsaturatedheterocyclic groups containing 1 to 4 nitrogen atoms such as, but notlimited to, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl; unsaturated 3 to 8membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atomssuch as, but not limited to, oxazolyl, isoxazolyl, oxadiazolyl (e.g.1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.);saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to3 nitrogen atoms such as, but not limited to, morpholinyl; unsaturatedcondensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl, benzoxazinyl(e.g. 2H-1,4-benzoxazinyl etc.); unsaturated 3 to 8 membered ringscontaining 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms such as, butnot limited to, thiazolyl, isothiazolyl, thiadiazolyl (e.g.1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.); saturated 3 to 8 membered rings containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to,thiazolodinyl; saturated and unsaturated 3 to 8 membered ringscontaining 1 to 2 sulfur atoms such as, but not limited to, thienyl,dihydrodithiinyl, dihydrodithionyl, tetrahydrothiophene,tetrahydrothiopyran; unsaturated condensed heterocyclic rings containing1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limitedto, benzothiazolyl, benzothiadiazolyl, benzothiazinyl (e.g.2H-1,4-benzothiazinyl, etc.), dihydrobenzothiazinyl (e.g.2H-3,4-dihydrobenzothiazinyl, etc.), unsaturated 3 to 8 membered ringscontaining oxygen atoms such as, but not limited to furyl; unsaturatedcondensed heterocyclic rings containing 1 to 2 oxygen atoms such asbenzodioxolyl (e.g. 1,3-benzodioxoyl, etc.); unsaturated 3 to 8 memberedrings containing an oxygen atom and 1 to 2 sulfur atoms such as, but notlimited to, dihydrooxathiinyl; saturated 3 to 8 membered ringscontaining 1 to 2 oxygen atoms and 1 to 2 sulfur atoms such as1,4-oxathiane; unsaturated condensed rings containing 1 to 2 sulfuratoms such as benzothienyl, benzodithiinyl; and unsaturated condensedheterocyclic rings containing an oxygen atom and 1 to 2 oxygen atomssuch as benzoxathiinyl. Heterocyclyl group also include those describedabove in which one or more S atoms in the ring is double bonded to oneor two oxygen atoms (sulfoxides and sulfones). For example, heterocyclylgroups include tetrahydrothiophene, tetrahydrothiophene oxide, andtetrahydrothiophene 1,1-dioxide. Preferred heterocyclyl groups contain 5or 6 ring members. More preferred heterocyclyl groups includemorpholine, piperazine, piperidine, pyrrolidine, imidazole, pyrazole,1,2,3-triazole, 1,2,4-triazole, tetrazole, thiomorpholine, pyrrole,homopiperazine, oxazolidin-2-one, pyrrolidin-2-one, oxazole, thiazole,isoxazole, furan, and tetrahydrofuran.

The phrase “substituted heterocyclyl” refers to an unsubstitutedheterocyclyl group as defined above in which one of the ring members isbonded to a non-hydrogen atom such as described above with respect tosubstituted alkyl groups and substituted aryl groups. Examples, include,but are not limited to, 2-methylbenzimidazolyl, 5-methylbenzimidazolyl,5-chlorobenzthiazolyl, 1-methyl piperazinyl, and 2-chloropyridyl amongothers.

The phrase “unsubstituted heterocyclylalkyl” refers to unsubstitutedalkyl groups as defined above in which a hydrogen or carbon bond of theunsubstituted alkyl group is replaced with a bond to a heterocyclylgroup as defined above. For example, methyl (—CH₃) is an unsubstitutedalkyl group. If a hydrogen atom of the methyl group is replaced by abond to a heterocyclyl group, such as if the carbon of the methyl werebonded to carbon 2 of pyridine (one of the carbons bonded to the N ofthe pyridine) or carbons 3 or 4 of the pyridine, then the compound is anunsubstituted heterocyclylalkyl group.

The phrase “substituted heterocyclylalkyl” has the same meaning withrespect to unsubstituted heterocyclylalkyl groups that substitutedaralkyl groups had with respect to unsubstituted aralkyl groups.However, a substituted heterocyclylalkyl group also includes groups inwhich a non-hydrogen atom is bonded to a heteroatom in the heterocyclylgroup of the heterocyclylalkyl group such as, but not limited to, anitrogen atom in the piperidine ring of a piperidinylalkyl group.

The phrase “unsubstituted alkylaminoalkyl” refers to an unsubstitutedalkyl group as defined above in which a carbon or hydrogen bond isreplaced by a bond to a nitrogen atom that is bonded to a hydrogen atomand an unsubstituted alkyl group as defined above. For example, methyl(—CH₃) is an unsubstituted alkyl group. If a hydrogen atom of the methylgroup is replaced by a bond to a nitrogen atom that is bonded to ahydrogen atom and an ethyl group, then the resulting compound is—CH₂—N(H)(CH₂CH₃) which is an unsubstituted alkylaminoalkyl group.

The phrase “substituted alkylaminoalkyl” refers to an unsubstitutedalkylaminoalkyl group as defined above except where one or more bonds toa carbon or hydrogen atom in one or both of the alkyl groups is replacedby a bond to a non-carbon or non-hydrogen atom as described above withrespect to substituted alkyl groups except that the bond to the nitrogenatom in all alkylaminoalkyl groups does not by itself qualify allalkylaminoalkyl groups as being substituted. However, substitutedalkylaminoalkyl groups does include groups in which the hydrogen bondedto the nitrogen atom of the group is replaced with a non-carbon andnon-hydrogen atom.

The phrase “unsubstituted dialkylaminoalkyl” refers to an unsubstitutedalkyl group as defined above in which a carbon bond or hydrogen bond isreplaced by a bond to a nitrogen atom which is bonded to two othersimilar or different unsubstituted alkyl groups as defined above.

The phrase “substituted dialkylaminoalkyl” refers to an unsubstituteddialkylaminoalkyl group as defined above in which one or more bonds to acarbon or hydrogen atom in one or more of the alkyl groups is replacedby a bond to a non-carbon and non-hydrogen atom as described withrespect to substituted alkyl groups. The bond to the nitrogen atom inall dialkylaminoalkyl groups does not by itself qualify alldialkylaminoalkyl groups as being substituted.

The phrase “unsubstituted heterocyclyloxyalkyl” refers to anunsubstituted alkyl group as defined above in which a carbon bond orhydrogen bond is replaced by a bond to an oxygen atom which is bonded toan unsubstituted heterocyclyl group as defined above.

The phrase “substituted heterocyclyloxyalkyl” refers to an unsubstitutedheterocyclyloxyalkyl group as defined above in which a bond to a carbonor hydrogen group of the alkyl group of the heterocyclyloxyalkyl groupis bonded to a non-carbon and non-hydrogen atom as described above withrespect to substituted alkyl groups or in which the heterocyclyl groupof the heterocyclyloxyalkyl group is a substituted heterocyclyl group asdefined above.

The phrase “unsubstituted arylaminoalkyl” refers to an unsubstitutedalkyl group as defined above in which a carbon bond or hydrogen bond isreplaced by a bond to a nitrogen atom which is bonded to at least oneunsubstituted aryl group as defined above.

The phrase “substituted arylaminoalkyl” refers to an unsubstitutedarylaminoalkyl group as defined above except where either the alkylgroup of the arylaminoalkyl group is a substituted alkyl group asdefined above or the aryl group of the arylaminoalkyl group is asubstituted aryl group except that the bonds to the nitrogen atom in allarylaminoalkyl groups does not by itself qualify all arylaminoalkylgroups as being substituted. However, substituted arylaminoalkyl groupsdoes include groups in which the hydrogen bonded to the nitrogen atom ofthe group is replaced with a non-carbon and non-hydrogen atom.

The phrase “unsubstituted heterocyclylaminoalkyl” refers to anunsubstituted alkyl group as defined above in which a carbon or hydrogenbond is replaced by a bond to a nitrogen atom which is bonded to atleast one unsubstituted heterocyclyl group as defined above.

The phrase “substituted heterocyclylaminoalkyl” refers to unsubstitutedheterocyclylaminoalkyl groups as defined above in which the heterocyclylgroup is a substituted heterocyclyl group as defined above and/or thealkyl group is a substituted alkyl group as defined above. The bonds tothe nitrogen atom in all heterocyclylaminoalkyl groups does not byitself qualify all heterocyclylaminoalkyl groups as being substituted.However, substituted heterocyclylaminoalkyl groups do include groups inwhich the hydrogen bonded to the nitrogen atom of the group is replacedwith a non-carbon and non-hydrogen atom.

The phrase “unsubstituted alkylaminoalkoxy” refers to an unsubstitutedalkyl group as defined above in which a carbon or hydrogen bond isreplaced by a bond to an oxygen atom which is bonded to the parentcompound and in which another carbon or hydrogen bond of theunsubstituted alkyl group is bonded to a nitrogen atom which is bondedto a hydrogen atom and an unsubstituted alkyl group as defined above.

The phrase “substituted alkylaminoalkoxy” refers to unsubstitutedalkylaminoalkoxy groups as defined above in which a bond to a carbon orhydrogen atom of the alkyl group bonded to the oxygen atom which isbonded to the parent compound is replaced by one or more bonds to anon-carbon and non-hydrogen atoms as discussed above with respect tosubstituted alkyl groups and/or if the hydrogen bonded to the aminogroup is bonded to a non-carbon and non-hydrogen atom and/or if thealkyl group bonded to the nitrogen of the amine is bonded to anon-carbon and non-hydrogen atom as described above with respect tosubstituted alkyl groups. The presence of the amine and alkoxyfunctionality in all alkylaminoalkoxy groups does not by itself qualifyall such groups as substituted alkylaminoalkoxy groups.

The phrase “unsubstituted dialkylaminoalkoxy” refers to an unsubstitutedalkyl group as defined above in which a carbon or hydrogen bond isreplaced by a bond to an oxygen atom which is bonded to the parentcompound and in which another carbon or hydrogen bond of theunsubstituted alkyl group is bonded to a nitrogen atom which is bondedto two other similar or different unsubstituted alkyl groups as definedabove.

The phrase “substituted dialkylaminoalkoxy” refers to an unsubstituteddialkylaminoalkoxy group as defined above in which a bond to a carbon orhydrogen atom of the alkyl group bonded to the oxygen atom which isbonded to the parent compound is replaced by one or more bonds to anon-carbon and non-hydrogen atoms as discussed above with respect tosubstituted alkyl groups and/or if one or more of the alkyl groupsbonded to the nitrogen of the amine is bonded to a non-carbon andnon-hydrogen atom as described above with respect to substituted alkylgroups. The presence of the amine and alkoxy functionality in alldialkylaminoalkoxy groups does not by itself qualify all such groups assubstituted dialkylaminoalkoxy groups.

The phrase “unsubstituted heterocyclyloxy” refers to a hydroxyl group(—OH) in which the bond to the hydrogen atom is replaced by a bond to aring atom of an otherwise unsubstituted heterocyclyl group as definedabove.

The phrase “substituted heterocyclyloxy” refers to a hydroxyl group(—OH) in which the bond to the hydrogen atom is replaced by a bond to aring atom of an otherwise substituted heterocyclyl group as definedabove.

The term “protected” with respect to hydroxyl groups, amine groups, andsulfhydryl groups refers to forms of these functionalities which areprotected from undesirable reaction with a protecting group known tothose skilled in the art such as those set forth in Protective Groups inOrganic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, NewYork, N.Y., (3rd Edition, 1999) which can be added or removed using theprocedures set forth therein. Examples of protected hydroxyl groupsinclude, but are not limited to, silyl ethers such as those obtained byreaction of a hydroxyl group with a reagent such as, but not limited to,t-butyldimethyl-chlorosilane, trimethylchlorosilane,triisopropylchlorosilane, triethylchlorosilane; substituted methyl andethyl ethers such as, but not limited to methoxymethyl ether,methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether,2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethylether, allyl ether, benzyl ether; esters such as, but not limited to,benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate.Examples of protected amine groups include, but are not limited to,amides such as, formamide, acetamide, trifluoroacetamide, and benzamide;imides, such as phthalimide, and dithiosuccinimide; and others. Examplesof protected sulfhydryl groups include, but are not limited to,thioethers such as S-benzyl thioether, and S-4-picolyl thioether;substituted S-methyl derivatives such as hemithio, dithio and aminothioacetals; and others.

A “pharmaceutically acceptable salt” includes a salt with an inorganicbase, organic base, inorganic acid, organic acid, or basic or acidicamino acid. As salts of inorganic bases, the invention includes, forexample, alkali metals such as sodium or potassium; alkaline earthmetals such as calcium and magnesium or aluminum; and ammonia. As saltsof organic bases, the invention includes, for example, trimethylamine,triethylamine, pyridine, picoline, ethanolamine, diethanolamine, andtriethanolamine. As salts of inorganic acids, the instant inventionincludes, for example, hydrochloric acid, hydroboric acid, nitric acid,sulfuric acid, and phosphoric acid. As salts of organic acids, theinstant invention includes, for example, formic acid, acetic acid,trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleicacid, citric acid, succinic acid, malic acid, methanesulfonic acid,benzenesulfonic acid, and p-toluenesulfonic acid. As salts of basicamino acids, the instant invention includes, for example, arginine,lysine and ornithine. Acidic amino acids include, for example, asparticacid and glutamic acid.

Compounds having the structure I, tautomers of the compounds,pharmaceutically acceptable salts of the compounds, and pharmaceuticallyacceptable salts of the tautomers have been found to inhibit VEGF-RTK.Structure I has the following formula.

In compounds of structure I, Y is selected from —OH, —OR⁸ groups, —SH,—SR⁹ groups, —NR¹⁰R¹¹ groups, —CN, —C(═O)—R¹² groups, substituted orunsubstituted alkyl groups, substituted or unsubstituted alkenyl groups,substituted or unsubstituted alkynyl groups, substituted orunsubstituted aralkyl groups, substituted or unsubstitutedheterocyclylalkyl groups, substituted or unsubstituted alkylaminoalkylgroups, substituted or unsubstituted dialkylaminoalkyl groups,substituted or unsubstituted arylaminoalkyl groups, substituted orunsubstituted diarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(alkyl)(heterocyclyl)aminoalkyl groups, substituted and unsubstituted(aryl)(heterocyclyl)aminoalkyl groups, substituted or unsubstitutedheterocyclyl groups, substituted or unsubstituted aryl groups,substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups. In more preferred compounds having thestructure I, Y is —OH, an —OR⁸ group, or a —NR¹⁰R¹¹ group. Morepreferably, Y is a —NR¹⁰R¹¹ group, where, one of R¹⁰ or R¹¹ is H orwhere R¹⁰ and R¹¹ are both H.

In yet other compounds having the structure I, Y is selected from—N(CH₃)₂, —NH(CH₃), —NH(CH₂CH₃), —N(CH₂CH₃)₂, —NH(aryl) groups,—N(aryl)₂ groups, —NHNH₂, —NHN(CH₃)₂, —N(CH₃)NH(CH₃), —NH(CH₂)_(m)NH₂groups, —NH(CH₂)_(m)NH(alkyl) groups, —NH(CH₂)_(m)N(alkyl)₂ groups,—N(alkyl)(CH₂)_(m)NH₂ groups, —N(alkyl)(CH₂)_(m)NH(alkyl) groups,—N(alkyl)(CH₂)_(m)N(alkyl)₂ groups, —NH(CH₂)_(n)(heterocyclyl) groups,—N(alkyl)[(CH₂)_(n)(heterocyclyl)] groups, —NH(CH₂)_(m)OH groups,—NH(CH₂)_(m)OCH₃ groups, —NHCH₂CH(NH₂)CH(CH₃)₂, —NH(₂-aminocyclohexyl),—NH(cyclohexyl), —NHOCH₃, —NH(N-morpholinyl), —NH(quinuclidyl),especially —NH(quinuclid-3-yl), and groups where R¹⁰ and R¹¹ join toform a substituted or unsubstituted saturated 5 or 6 memberedN-containing ring, where m is 2, 3, or 4 and n is 0, 1, 2, or 3. Stillmore preferred compounds of this type are compounds in which Y is—NH(5-benzimidazolyl), —NH(CH₂)₂N(CH₃)₂, —NH(CH₂)₂OH,—NH(CH₂)(4-imidazolyl), —NH(CH₂)(3-imidazolyl), —NH(CH₂)(4-pyridyl),—NH(CH₂)(2-pyridyl), —NH(CH₂)(3-pyridyl), —NH(CH₂)(2-tetrahydrofuranyl),—NH(CH₂)(4-piperidinyl), —NH(CH₂)(3-piperidinyl),—NH(CH₂)₂[2-(N-methyl-pyrrolidinyl)], —NH(CH₂)₂(2-pyrrolidinyl),—NH(CH₂)[2-(N-methylpyrrolidinyl)], —NH(CH₂)(2-pyrrolidinyl),—NH(3-piperidinyl), or —NH(3-pyrrolidinyl).

Z is O, S, or a NR¹³ group in compounds of structure I. Preferably, Z isa NR¹³ group and, even more preferably, R¹³ is H.

In compounds of structure I, R¹ and R² join to form a 5 to 7 memberedsubstituted or unsubstituted ring including at least one O, N, or Satom. In some embodiments, R¹ and R² join together to form a 5 or 6membered substituted or unsubstituted ring including one N atom, one Oatom, or one S atom. In other embodiments R¹ and R² join together toform a 5 or 6 membered ring including two heteroatoms selected from O,N, or S. An example of an embodiment in which R¹ and R² join together toform a 5 membered ring having two N atoms are compounds having theformula IA described below. Another example of an embodiment in which R¹and R² join together to form a 5 membered ring having two N atoms arecompounds having the formula IB described below. An example of anembodiment in which R¹ and R² form a 5 membered ring having one S atomare compounds having the formula IC described below. Examples ofembodiments in which R¹ and R² join together to form a 6 membered ringcontaining one or more N atom are compounds having the formula II below.

R³ and R¹³ may be the same or different in compounds of structure I andmay be H, —OH, substituted or unsubstituted alkoxy groups, substitutedor unsubstituted aryloxy groups, —NH₂, substituted or unsubstitutedalkylamino groups, substituted or unsubstituted arylamino groups,substituted or unsubstituted dialkylamino groups, substituted orunsubstituted diarylamino groups, substituted or unsubstituted(alkyl)(aryl)amino groups, substituted and unsubstitutedheterocyclylamino groups, substituted and unsubstituteddiheterocyclylamino groups, substituted and unsubstituted(alkyl)(heterocyclyl)amino groups, substituted and unsubstituted(aryl)(heterocyclyl)amino groups, substituted and unsubstitutedheterocylyloxy groups, substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, —C(═O)H, —C(═O)-alkyl groups,or —C(═O)-aryl groups. In more preferred compounds of structure I, R³ isH.

R⁴, R⁵, R⁶, and R⁷ may be the same or different in compounds ofstructure I and are independently selected from H, Cl, Br, F, I, —NO₂,—CN, —OH, —OR¹⁴ groups, —NR¹⁵R¹⁶ groups, —C(═O)R¹⁷ groups, —SH, —SR¹⁸groups, —S(═O)R¹⁹ groups, S(═O)₂R²⁰ groups, substituted or unsubstitutedamidinyl groups, substituted or unsubstituted guanidinyl groups,substituted or unsubstituted primary, secondary, or tertiary alkylgroups, substituted or unsubstituted aryl groups, substituted orunsubstituted alkenyl groups, substituted or unsubstituted alkynylgroups, substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted alkylaminoalkyl groups, substituted or unsubstituteddialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkylgroups, substituted or unsubstituted diarylaminoalkyl groups,substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substitutedor unsubstituted heterocyclylalkyl groups, substituted or unsubstitutedaminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkylgroups, substituted and unsubstituted diheterocyclylaminoalkyl groups,substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups,substituted and unsubstituted (aryl)(heterocyclyl)aminoalkyl groups,substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups. R⁴ and R⁵ may join to form a 5 to 7membered substituted or unsubstituted carbocyclic or heterocyclic ring.Similarly, R⁵ and R⁶ may join to form a 5 to 7 membered substituted orunsubstituted carbocyclic or heterocyclic ring. Finally, R⁶ and R⁷ mayalso join to form a 5 to 7 membered substituted or unsubstitutedcarbocyclic or heterocyclic ring.

In one group of preferred compounds of structure I, R⁴, R⁵, R⁶, and R⁷are all H. In other more preferred compounds of structure I, R⁵, R⁶ orboth R⁵ and R⁶ are alkyl groups having from one to four carbon atoms. Instill other preferred compounds having the formula of structure I, R⁵ orR⁶ is an —OR¹⁴ group and R¹⁴ is an alkyl, aryl, heterocyclyl, orheterocyclylalkyl group. In still further preferred compounds ofstructure I, R⁵ or R⁶ is a —OCH₂(CH₂)_(q)(heterocyclyl) group where q is0, 1, 2, 3, or 4. More preferably the heterocyclyl group of the—OCH₂(CH₂)_(q)(heterocyclyl) group is a heterocycle selected fromsubstituted or unsubstituted morpholine, substituted or unsubstitutedpiperazine, substituted or unsubstituted piperidine, substituted orunsubstituted pyrrolidine, substituted or unsubstituted pyrrole,substituted or unsubstituted imidazole, substituted or unsubstitutedpyrazole, substituted or unsubstituted 1,2,3-triazole, substituted orunsubstituted 1,2,4-triazole, substituted or unsubstituted tetrazole,substituted or unsubstituted thiomorpholine, substituted orunsubstituted homopiperazine, substituted or unsubstitutedoxazolidin-2-one, substituted or unsubstituted pyrrolidin-2-one,substituted or unsubstituted pyridine, substituted or unsubstitutedoxazole, substituted or unsubstituted isoxazole, substituted orunsubstituted thiazole, substituted or unsubstituted isothiazole,substituted or unsubstituted furan, substituted or unsubstitutedthiophene, substituted or unsubstituted tetrahydrofuran, substituted orunsubstituted tetrahydrothiophene, substituted or unsubstitutedbenzimidazole, substituted or unsubstituted benzoxazole, or substitutedor unsubstituted benzothiazole.

In still other preferred compounds having the structure I, at least oneof R⁴, R⁵, R⁶, or R⁷ is a substituted or unsubstituted heterocyclylgroup, more specifically a substituted or unsubstituted heterocyclylgroup comprising at least one O or N atom, and more particularly asubstituted or unsubstituted heterocyclyl group selected frommorpholine, piperazine, piperidine, 1,2,3-triazole, 1,2,4-triazole,tetrazole, pyrrolidine, pyrazole, pyrrole, thiomorpholine,homopiperazine, benzimidazole, oxazolidin-2-one, pyrrolidin-2-one,imidazole, isoxazole, oxazole, isothiazole, thiazole, thiophene, furan,pyran, tetrahydrothiophene, tetrahydrofuran, tetrahydropyran, andpyridine.

In groups including heterocyclyl groups, the heterocycle may be attachedin various ways. For example in the —OCH₂(CH₂)_(q)(heterocyclyl) group,the heterocyclyl group may be bonded to a methylene carbon of the—OCH₂(CH₂)_(q) group of the —OCH₂(CH₂)_(q)(heterocyclyl) group throughvarious ring members. By way of non-limiting example, where q is 1 andthe heterocyclyl group is tetrahydrofuran, the group could berepresented by the formula —OCH₂CH₂-(tetrahydrofuranyl) whichcorresponds to the following two structures:

where structure IV represents the group that can be referred to as the—OCH₂CH₂(2-tetrahydrofuranyl) group and structure V represents the groupthat can be referred to as the —OCH₂CH₂(3-tetrahydrofuranyl) group. Whenthe heterocyclyl group is a N-containing heterocycle, such as, but notlimited to piperidine, piperazine, morpholine, or pyrrolidine, theheterocycle can be bonded to the methylene carbon through a ring carbonatom or through a nitrogen atom in the ring of the N-containingheterocycle. Both of these are preferred. Where the heterocyclyl groupis a piperidine and q is 2 for a —OCH₂(CH₂)_(q)(heterocyclyl) group, thefollowing structures are possible and preferred:

Structure VI is an example of a —O(CH₂)₃(N-piperidinyl) or—O(CH₂)₃(1-piperidinyl) group. Structure VII is an example of a—O(CH₂)₃(2-piperidinyl) group. Structure VIII is an example of a—O(CH₂)₃(3-piperidinyl) group. Structure IX is an example of a—O(CH₂)₃(4-piperidinyl) group. Where the heterocyclyl group is apiperazine and q is 1 for an —OCH₂(CH₂)_(q)(heterocyclyl) group, thefollowing structures are possible and preferred:

Structure X is an example of a —O(CH₂)₂(2-piperazinyl) group, andstructure XI is an example of a —O(CH₂)₂(1-piperazinyl) or—O(CH₂)₂(N-piperazinyl)group. Where the heterocyclyl group is amorpholine and q is 1 for an —OCH₂(CH₂)_(q)-(heterocyclyl) group, thefollowing structures are possible and preferred:

Structure XII is an example of a —O(CH₂)₂(3-morpholinyl) group,structure XIII is an example of a —O(CH₂)₂(4-morpholinyl) or—O(CH₂)₂(N-morpholinyl) group, and structure XIV is an example of a—O(CH₂)₂(2-morpholinyl) group. It will be observed that where the groupis a pyrrolidine, and q is 1, the structures available include—O(CH₂)₂(1-pyrrolidinyl) or —O(CH₂)₂(N-pyrrolidinyl),—O(CH₂)₂(2-pyrrolidinyl), and —O(CH₂)₂(3-pyrrolidinyl).

In compounds of structure I, R⁸ may be a substituted or unsubstitutedalkyl group, a substituted or unsubstituted aryl group, a substituted orunsubstituted heterocyclyl group, a substituted or unsubstitutedheterocyclylalkyl group, —C(═O)H, a —C(═O)-alkyl group, a —C(═O)-arylgroup, a —C(═O)O-alkyl group, a —C(═O)O-aryl group, —C(═O)NH₂, a—C(═O)NH(alkyl) group, a —C(═O)NH(aryl) group, a —C(═O)N(alkyl)₂ group,a —C(═O)N(aryl)₂ group, a —C(═O)N(alkyl)(aryl) group, —NH₂, a —NH(alkyl)group, a —NH(aryl) group, a —N(alkyl)₂ group, a —N(alkyl)(aryl) group, a—N(aryl)₂ group, a —C(═O)NH(heterocyclyl) group, a—C(═O)N(heterocyclyl)₂ group, a —C(═O)N(alkyl)(heterocyclyl) group, or a—C(═O)N(aryl)(heterocyclyl) group.

R⁹ and R¹⁸ may be the same or different in compounds of structure I andare independently selected from substituted or unsubstituted alkylgroups, or substituted or unsubstituted aryl groups.

In compounds of structure I, R¹⁰ is selected from H, substituted orunsubstituted alkyl groups, substituted or unsubstituted aryl groups, orsubstituted or unsubstituted heterocyclyl groups, and R¹¹ is selectedfrom H, substituted or unsubstituted alkyl groups, substituted orunsubstituted aryl groups, substituted or unsubstituted heterocyclylgroups, —OH, alkoxy groups, aryloxy groups, —NH₂, substituted orunsubstituted heterocyclylalkyl groups, substituted or unsubstitutedaminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups,substituted or unsubstituted dialkylaminoalkyl groups, substituted orunsubstituted arylaminoalkyl groups, substituted or unsubstituteddiarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkylaminogroups, substituted or unsubstituted arylamino groups, substituted orunsubstituted dialkylamino groups, substituted or unsubstituteddiarylamino groups, substituted or unsubstituted (alkyl)(aryl)aminogroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkylgroups, —C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,—C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —C(═O)-heterocyclyl groups,—C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,—C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups,—C(═O)—N(aryl)(heterocyclyl) groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(alkyl)(heterocyclyl)aminoalkyl groups, substituted and unsubstituted(aryl)(heterocyclyl)aminoalkyl groups, substituted or unsubstitutedhydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups,substituted or unsubstituted aryloxyalkyl groups, or substituted orunsubstituted heterocyclyloxyalkyl groups. R¹⁰ and R¹¹ may join togetherto form a 5 to 7 membered saturated or unsaturated, substituted orunsubstituted N-containing ring.

In compounds of structure I, R¹² is selected from H, —OH, alkoxy groups,aryloxy groups, —NH₂, —NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂groups, —N(aryl)₂ groups, —N(alkyl)(aryl) groups, substituted orunsubstituted alkyl groups, substituted or unsubstituted aryl groups,—NH(heterocyclyl) groups, —N(heterocyclyl)₂ groups,—N(alkyl)(heterocyclyl) groups, or —N(aryl)(heterocyclyl) groups.

In structure I, R¹⁴ is selected from substituted or unsubstituted alkylgroups, substituted or unsubstituted aryl groups, substituted orunsubstituted heterocyclyl groups, substituted or unsubstitutedheterocyclylalkyl groups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-arylgroups, —C(═O)-heterocyclyl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,—C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —C(═O)NH-heterocyclyl groups,—C(═O)N-(heterocyclyl)₂ groups, —C(═O)N(alkyl)(heterocyclyl) groups,—C(═O)N(aryl)(heterocyclyl) groups, substituted or unsubstitutedaminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups,substituted or unsubstituted dialkylaminoalkyl groups, substituted orunsubstituted arylaminoalkyl groups, substituted or unsubstituteddiarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted or unsubstituteddiheterocyclylaminoalkyl groups, substituted or unsubstituted(heterocyclyl)(alkyl)aminoalkyl groups, substituted or unsubstituted(heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstitutedalkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups,substituted or unsubstituted hydroxyalkyl groups, or substituted orunsubstituted heterocyclyloxyalkyl groups.

In compounds of structure I, R¹⁵ is selected from H, substituted orunsubstituted alkyl groups, substituted or unsubstituted aryl groups, orsubstituted or unsubstituted heterocyclyl groups. R¹⁶ is selected fromH, substituted or unsubstituted alkyl groups, substituted orunsubstituted aryl groups, substituted or unsubstituted heterocyclylgroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)NH₂,—C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups,—C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups, —C(═O)O-alkylgroups, —C(═O)O-aryl groups, substituted or unsubstituted aminoalkylgroups, substituted or unsubstituted alkylaminoalkyl groups, substitutedor unsubstituted dialkylaminoalkyl groups, substituted or unsubstitutedarylaminoalkyl groups, substituted or unsubstituted diarylaminoalkylgroups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups,substituted or unsubstituted heterocyclylalkyl groups,—C(═O)-heterocyclyl groups, —C(═O)—O-heterocyclyl groups,—C(═O)NH(heterocyclyl) groups, —C(═O)—N(heterocyclyl)₂ groups,—C(═O)—N(alkyl)(heterocyclyl) groups, —C(═O)—N(aryl)(heterocyclyl)groups, substituted or unsubstituted heterocyclylaminoalkyl groups,substituted and unsubstituted diheterocyclylaminoalkyl groups,substituted and unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups,substituted and unsubstituted (heterocyclyl)(aryl)aminoalkyl groups,substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups. R¹⁵ and R¹⁶ may join together to form a 5to 7 membered saturated or unsaturated, substituted or unsubstitutedN-containing ring.

R¹⁷, R¹⁹, and R²⁰ may be the same or different and are independentlyselected from H, —NH₂, —NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂groups, —N(aryl)₂ groups, —N(alkyl)(aryl) groups, —NH(heterocyclyl)groups, —N(heterocyclyl)(alkyl) groups, —N(heterocyclyl)(aryl) groups,—N(heterocyclyl)₂ groups, substituted and unsubstituted alkyl groups,substituted and unsubstituted aryl groups, —OH, substituted andunsubstituted alkoxy groups, substituted and unsubstituted heterocyclylgroups, substituted and unsubstituted aryloxy groups, heterocyclyloxygroups, —NHOH, —N(alkyl)OH groups, —N(aryl)OH groups, —N(alkyl)O-alkylgroups, —N(aryl)O-alkyl groups, —N(alkyl)O-aryl groups, and—N(aryl)O-aryl groups.

In some preferred compounds of structure I, R¹⁷ is selected fromunsubstituted alkyl groups, substituted or unsubstituted aryl groups,—NH₂, —NH(alkyl) groups, —N(alkyl)₂ groups, —NH(aryl) groups, —N(aryl)₂groups, —N(alkyl)(aryl) groups, —NH(heterocyclyl) groups,—N(heterocyclyl)(alkyl) groups, —N(heterocyclyl)(aryl) groups,—N(heterocyclyl)₂ groups, or N-containing heterocycles, and theN-containing heterocycles are bonded to the carbonyl carbon of the—C(═O)—R¹⁷ group through either a nitrogen atom or a carbon atom in therings of the N-containing heterocycles. In still more preferredcompounds in which R¹⁷ is a N-containing heterocycle, the N-containingheterocycle of the R¹⁷ group is selected from substituted orunsubstituted morpholine, substituted or unsubstituted pyrrolidine,substituted or unsubstituted piperazine, substituted or unsubstitutedpiperidine, substituted or unsubstituted pyrrole, substituted orunsubstituted imidazole, substituted or unsubstituted pyrazole,substituted or unsubstituted 1,2,3-triazole, substituted orunsubstituted 1,2,4-triazole, substituted or unsubstituted tetrazole,substituted or unsubstituted thiomorpholine, substituted orunsubstituted homopiperazine, substituted or unsubstitutedoxazolidin-2-one, substituted or unsubstituted pyrrolidin-2-one,substituted or unsubstituted pyridine, substituted or unsubstitutedoxazole, substituted or unsubstituted isoxazole, substituted orunsubstituted thiazole, substituted or unsubstituted isothiazole,substituted or unsubstituted benzimidazole, substituted or unsubstitutedbenzoxazole, or substituted or unsubstituted benzothiazole.

In other preferred compounds having structure I, R¹⁴ or R¹⁶ is selectedfrom substituted or unsubstituted aminoalkyl groups, substituted orunsubstituted alkylaminoalkyl groups, substituted or unsubstitutedarylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkylgroups, substituted or unsubstituted diarylaminoalkyl groups,alkylarylaminoalkyl groups, or substituted or unsubstitutedheterocycylalkyl groups, including: —CH₂(CH₂)_(p)NH₂ groups,—CH₂(CH₂)_(p)NH(alkyl) groups, —CH₂(CH₂)_(p)NH(aryl) groups,—CH₂(CH₂)_(p)N(alkyl)₂ groups, —CH₂(CH₂)_(p)N(aryl)₂ groups,—CH₂(CH₂)_(p)N(alkyl)(aryl) groups, or —CH₂(CH₂)_(p)(heterocyclyl)groups, where p is an integer ranging from 0 to 4 and the heterocyclylgroup of the —CH₂(CH₂)_(p)(heterocyclyl) group is a N-containingheterocycle selected from substituted or unsubstituted morpholine,substituted or unsubstituted pyrrolidine, substituted or unsubstitutedpiperazine, substituted or unsubstituted piperidine, substituted orunsubstituted pyrrole, substituted or unsubstituted imidazole,substituted or unsubstituted pyrazole, substituted or unsubstituted1,2,3-triazole, substituted or unsubstituted 1,2,4-triazole, substitutedor unsubstituted tetrazole, substituted or unsubstituted thiomorpholine,substituted or unsubstituted homopiperazine, substituted orunsubstituted oxazolidin-2-one, substituted or unsubstitutedpyrrolidin-2-one, substituted or unsubstituted pyridine, substituted orunsubstituted oxazole, substituted or unsubstituted isoxazole,substituted or unsubstituted thiazole, substituted or unsubstitutedisothiazole, substituted or unsubstituted benzimidazole, substituted orunsubstituted benzoxazole, or substituted or unsubstitutedbenzothiazole.

Other compounds having the structure I are provided that also have thestructure IA. These are compounds in which R¹ and R² of structure I jointogether to form a 5 membered ring having having two N atoms.

In compounds of structure IA, R²¹ is selected from H or substituted orunsubstituted alkyl groups; R²² may be the same or different from R⁴,R⁵, R⁶, R⁷ and is independently selected from H, Cl, Br, F, I, —NO₂,—CN, —OH, —OR¹⁴ groups, —NR¹⁵R¹⁶ groups, —C(═O)R¹⁷ groups, —SH, —SR¹⁸groups, —S(═O)R¹⁹ groups, S(═O)₂R²⁰ groups, substituted or unsubstitutedamidinyl groups, substituted or unsubstituted guanidinyl groups,substituted or unsubstituted primary, secondary, or tertiary alkylgroups, substituted or unsubstituted aryl groups, substituted orunsubstituted alkenyl groups, substituted or unsubstituted alkynylgroups, substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted alkylaminoalkyl groups, substituted or unsubstituteddialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkylgroups, substituted or unsubstituted diarylaminoalkyl groups,substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substitutedor unsubstituted heterocyclylalkyl groups, substituted or unsubstitutedaminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkylgroups, substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups; and R³ through R²¹ have the valuesdescribed above with respect to compounds of structure I.

Other compounds of structure IA are those in which Z is an NR¹³ and morepreferably where R¹³ is H. Other compounds of structure IA are providedin which R³ is H.

Still other compounds of structure IA are those in which Y is an—NR¹⁰R¹¹ group. In still other compounds of structure IA, Y is an—NR¹⁰R¹¹ group and R¹⁰ and R¹¹ are hydrogen atoms.

Still other compounds having the structure I are provided that have thestructure IB. Like compounds of structure IA, these are compounds inwhich R¹ and R² of structure I join together to form a 5 membered ringhaving having two N atoms.

In compounds of structure IB, R²¹ is selected from H or substituted orunsubstituted alkyl groups; R²² may be the same or different from R⁴,R⁵, R⁶, R⁷ and is independently selected from H, Cl, Br, F, I, —NO₂,—CN, —OH, —OR¹⁴ groups, —NR¹⁵R¹⁶ groups, —C(═O)R¹⁷ groups, —SH, —SR¹⁸groups, —S(═O)R¹⁹ groups, S(═O)₂R²⁰ groups, substituted or unsubstitutedamidinyl groups, substituted or unsubstituted guanidinyl groups,substituted or unsubstituted primary, secondary, or tertiary alkylgroups, substituted or unsubstituted aryl groups, substituted orunsubstituted alkenyl groups, substituted or unsubstituted alkynylgroups, substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted alkylaminoalkyl groups, substituted or unsubstituteddialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkylgroups, substituted or unsubstituted diarylaminoalkyl groups,substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substitutedor unsubstituted heterocyclylalkyl groups, substituted or unsubstitutedaminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkylgroups, substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups; and R³ through R²¹ have the valuesdescribed above with respect to compounds of structure I.

Other compounds of structure IB include those in which Z is an NR¹³ andmore preferably those where R¹³ is H. Other compounds of structure IBare those in which R³ is H.

Still other compounds of structure IB are those in which Y is an—NR¹⁰R¹¹ group. In still other compounds of structure IB, Y is an—NR¹⁰R¹¹ group and R¹⁰ and R¹¹ are hydrogen atoms.

Still other compounds having the structure I are provided that have thestructure IC. These are compounds in which R¹ and R² of structure I jointogether to form a 5 membered ring having having one S atom.

In compounds of structure IC, R²¹ and R²² may be the same or differentfrom R⁴, R⁵, R⁶, R⁷ and each other and are independently selected fromH, Cl, Br, F, I, —NO₂, —CN, —OH, —OR¹⁴ groups, —NR¹⁵R¹⁶ groups,—C(═O)R¹⁷ groups, —SH, —SR¹⁸ groups, —S(═O)R¹⁹ groups, S(═O)₂R²⁰ groups,substituted or unsubstituted amidinyl groups, substituted orunsubstituted guanidinyl groups, substituted or unsubstituted primary,secondary, or tertiary alkyl groups, substituted or unsubstituted arylgroups, substituted or unsubstituted alkenyl groups, substituted orunsubstituted alkynyl groups, substituted or unsubstituted heterocyclylgroups, substituted or unsubstituted alkylaminoalkyl groups, substitutedor unsubstituted dialkylaminoalkyl groups, substituted or unsubstitutedarylaminoalkyl groups, substituted or unsubstituted diarylaminoalkylgroups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups,substituted or unsubstituted heterocyclylalkyl groups, substituted orunsubstituted aminoalkyl groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkylgroups, substituted or unsubstituted alkoxyalkyl groups, substituted orunsubstituted aryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups; and R³ through R²⁰ have the valuesdescribed above with respect to compounds of structure I.

Other compounds of structure IC are those in which Z is an NR¹³ and morepreferably those where R¹³ is H. Other compounds of structure IC arethose in which R³ is H.

Still other compounds of structure IC are those in which Y is an—NR¹⁰R¹¹ group. In still other compounds of structure IC, Y is an—NR¹⁰R¹¹ group and R¹⁰ and R¹¹ are hydrogen atoms.

Particularly preferred inhibitors of VEGF-RTK are compounds having thestructure II, tautomers of the compounds, pharmaceutically acceptablesalts of the compounds, and pharmaceutically acceptable salts of thetautomers. These are compounds having a ring system similar to that ofStructure I where R¹ and R², as defined above with respect to StructureI, join together to form a 6 membered ring that includes at least one Natom. Structure II has the following formula:

In compounds of structure II, W¹, W², W³, and W⁴ are selected from C orN, and at least one of W¹, W², W³, or W⁴ is N. In some preferredcompounds of structure II, W¹ is N and R¹ is absent or H. In otherpreferred compounds of structure II, W² is N and R² is absent or H. Instill other preferred compounds of structure II, W³ is N and R³ isabsent or H. In yet other preferred compounds of structure II, W⁴ is Nand R⁴ is absent or H. In some preferred compounds of structure II, oneof W¹, W², W³, and W⁴ is N. In other preferred compounds of structureII, two of W¹, W², W³, and W⁴ are N. In yet other preferred embodiments,W¹, W², and W³ are all C and W⁴ is N; W¹, W², and W⁴ are all C and W³ isN; W¹, W³, and W⁴ are all C and W² is N; or W², W³, and W⁴ are all C andW¹ is N.

In compounds having structure II, Y is selected from —OH, —OR¹⁰ groups,—SH, —SR¹¹ groups, —NR¹²R¹³ groups, —CN, —C(═O)—R¹⁴ groups, substitutedor unsubstituted alkyl groups, substituted or unsubstituted alkenylgroups, substituted or unsubstituted alkynyl groups, substituted orunsubstituted aralkyl groups, substituted or unsubstitutedheterocyclylalkyl groups, substituted or unsubstituted alkylaminoalkylgroups, substituted or unsubstituted dialkylaminoalkyl groups,substituted or unsubstituted arylaminoalkyl groups, substituted orunsubstituted diarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(heterocyclyl)(alkyl)aminoalkyl groups, substituted and unsubstituted(heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstitutedheterocyclyl groups, substituted or unsubstituted aryl groups,substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups.

In preferred compounds of structure II, Y is selected from —OH, —OR¹⁰groups, or —NR¹²R¹³ groups, or more preferably —NR¹²R¹³ groups, or stillmore preferably —NR¹²R¹³ groups where one or both of R¹² and R¹³ are H.In other preferred compounds having the structure II, Y is selected from—N(CH₃)₂, —NH(CH₃), —NH(CH₂CH₃), —N(CH₂CH₃)₂, —NH(aryl) groups,—N(aryl)₂ groups, —NHNH₂, —NHN(CH₃)₂, —N(CH₃)NH(CH₃), —NH(CH₂)_(m)NH₂groups, —NH(CH₂)_(m)NH(alkyl) groups, —NH(CH₂)_(m)N(alkyl)₂ groups,—N(alkyl)(CH₂)_(m)NH₂ groups, —N(alkyl)(CH₂)_(m)NH(alkyl) groups,—N(alkyl)(CH₂)_(m)N(alkyl)₂ groups, —NH(CH₂)_(n)(heterocyclyl) groups,—N(alkyl)[(CH₂)_(n)(heterocyclyl)] groups, —NH(CH₂)_(m)OH groups,—NH(CH₂)_(m)OCH₃ groups, —NHCH₂CH(NH₂)CH(CH₃)₂, —NH(2-aminocyclohexyl),—NH(cyclohexyl), —NHOCH₃, —NH(N-morpholinyl), —NH(quinuclidyl),especially —NH(quinuclid-3-yl),and groups where R¹² and R¹³ join to forma substituted or unsubstituted saturated 5 or 6 membered N-containingring, where m is 2, 3, or 4 and n is 0, 1, 2, or 3. Still more preferredcompounds of this type are those in which Y is selected from—NH(5-benzimidazolyl), —NH(CH₂)₂N(CH₃)₂, —NH(CH₂)₂OH,—NH(CH₂)(4-imidazolyl), —NH(CH₂)(3-imidazolyl), —NH(CH₂)(4-pyridyl),—NH(CH₂)(2-pyridyl), —NH(CH₂)(3-pyridyl), —NH(CH₂)(2-tetrahydrofuranyl),—NH(CH₂)(4-piperidinyl), —NH(CH₂)(3-piperidinyl),—NH(CH₂)₂[2-(N-methyl-pyrrolidinyl)], —NH(CH₂)₂(2-pyrrolidinyl),—NH(CH₂)[2-(N-methylpyrrolidinyl)], —NH(CH₂)(2-pyrrolidinyl),—NH(3-piperidinyl), or —NH(3-pyrrolidinyl).

In compound of structure II, Z is O, S, and NR¹⁵ groups. In preferredcompounds of structure II, Z is an NR¹⁵ group or more preferably is anNR¹⁵ group where R¹⁵ is H.

In compounds of structure II, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ may bethe same or different and are independently selected from H, Cl, Br, F,I, —NO₂, —CN, —OH, —OR¹⁶ groups, —NR¹⁷R¹⁸ groups, —C(═O)R¹⁹ groups, —SH,—SR²⁰ groups, —S(═O)R²¹ groups, S(═O)₂R²² groups, substituted orunsubstituted amidinyl groups, substituted or unsubstituted guanidinylgroups, substituted or unsubstituted primary, secondary, or tertiaryalkyl groups, substituted or unsubstituted aryl groups, substituted orunsubstituted alkenyl groups, substituted or unsubstituted alkynylgroups, substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted alkylaminoalkyl groups, substituted or unsubstituteddialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkylgroups, substituted or unsubstituted diarylaminoalkyl groups,substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substitutedor unsubstituted heterocyclylalkyl groups, substituted or unsubstitutedaminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkylgroups, substituted and unsubstituted diheterocyclylaminoalkyl groups,substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups,substituted and unsubstituted (aryl)(heterocyclyl)aminoalkyl groups,substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups, and R¹ is absent or H if W¹ is N, R² isabsent or H if W² is N, R³ is absent or H if W³ is N, and R⁴ is absentor H if W⁴ is N.

Some preferred compounds have the structure II where at least one of R¹,R², R³, R⁴, R⁵, R⁶, R⁷, or R⁸ is a substituted or unsubstitutedheterocyclyl group, and in more preferred embodiments, a substituted orunsubstituted heterocyclyl group selected from morpholine, piperazine,piperidine, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyrrolidine,pyrazole, pyrrole, thiomorpholine, homopiperazine, benzimidazole,oxazolidin-2-one, pyrrolidin-2-one, imidazole, isothiazole, thiazole,thiophene, furan, pyran, tetrahydrothiophene, tetrahydrofuran,tetrahydropyran, and pyridine.

Still other preferred compounds having structure II are those in whichR¹, R², and R³ are H, and W⁴ is N. Still other compounds having theformula of structure II are provided in which R², R³, and R⁴ are H, andW¹ is N. Still other compounds having the formula of structure II areprovided in which R¹, R³, and R⁴ are H, and W² is N. Still othercompounds having the formula of structure II are provided in which R¹,R², and R⁴ are H, and W³ is N.

In other preferred compounds, R¹ or R² is selected from F, Cl,substituted or unsubstituted alkoxy groups, substituted or unsubstitutedheterocyclyloxy groups, substituted or unsubstituted heterocyclylalkoxygroups, substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted alkyl-, heterocycyl-, or aryl-aminoalkyl groups,substituted or unsubstituted dialkyl- or diaryl-aminoalkyl groups,substituted or unsubstituted alkylarylaminoalkyl groups, substituted orunsubstituted alkyl- and aryl-aminoalkoxy groups, substituted orunsubstituted dialkyl- and diaryl-aminoalkoxy groups, or substituted orunsubstituted alkylarylaminoalkoxy groups. Particular examples include:—C(═O)N(alkyl)₂ groups, —OCH₂CH₂(N-morpholinyl), N-morpholinyl,—OCH₂CH₂N(alkyl)₂ groups, —OCH₂CH₂NH(alkyl) groups, —OCH₂CH₂NH₂,—OCH₂CH₂NH(aryl) groups, —OCH₂CH₂N(aryl)₂ groups, alkoxy groups,—OCH₂CH₂N(alkyl)(aryl) groups, —O(4-piperidinyl),—O[4-(1-alkyl)piperidinyl] groups, —OCH₂(2-pyridyl), —O(3-pyrrolidinyl),or —O[3-(1-alkyl)pyrrolidinyl] groups.

Still other preferred compounds include those in which R² is selectedfrom F, Cl, —NO₂, substituted or unsubstituted alkoxy groups,substituted or unsubstituted heterocyclylalkoxy groups, substituted orunsubstituted heterocyclyl groups, substituted or unsubstituted alkyl-,heterocycyl-, or aryl-aminoalkyl groups, substituted or unsubstituteddialkyl- and diaryl-aminoalkyl groups, substituted or unsubstitutedalkylarylaminoalkyl groups, substituted or unsubstituted alkyl- andaryl-aminoalkoxy groups, substituted or unsubstituted dialkyl- anddiaryl-aminoalkoxy groups, substituted or unsubstitutedalkylarylaminoalkoxy groups. Particular examples include: —OCH₃,N-morpholinyl, —N-cis-dialkylmorpholinyl, —N-(4-alkyl)piperazinyl, or—OCH₂(2-pyridyl).

In yet preferred compounds having structure II, R⁵, R⁶, R⁷, and R⁸ arehydrogen. In still other more preferred compounds of structure II, R⁶,R⁷ or both R⁶ and R⁷ are alkyl groups having from one to four carbonatoms. In yet other preferred compounds of structure II, R⁶ or R⁷ is an—OR¹⁶ group and R¹⁶ is an alkyl, aryl, heterocyclyl, orheterocyclylalkyl group. In still further preferred compounds ofstructure II, R⁶ or R⁷ is a —OCH₂(CH₂)_(q)(heterocyclyl) group and q is0, 1, 2, 3, or 4. In more preferred compounds in which R⁶ or R⁷ is a—OCH₂(CH₂)_(q)-(heterocyclyl) group, the heterocyclyl group of the—OCH₂(CH₂)_(n)(heterocyclyl) group is a heterocycle selected fromsubstituted or unsubstituted morpholine, substituted or unsubstitutedpiperazine, substituted or unsubstituted piperidine, substituted orunsubstituted pyrrolidine, substituted or unsubstituted pyrrole,substituted or unsubstituted imidazole, substituted or unsubstitutedpyrazole, substituted or unsubstituted 1,2,3-triazole, substituted orunsubstituted 1,2,4-triazole, substituted or unsubstituted tetrazole,substituted or unsubstituted thiomorpholine, substituted orunsubstituted homopiperazine, substituted or unsubstitutedoxazolidin-2-one, substituted or unsubstituted pyrrolidin-2-one,substituted or unsubstituted pyridine, substituted or unsubstitutedoxazole, substituted or unsubstituted isoxazole, substituted orunsubstituted thiazole, substituted or unsubstituted isothiazole,substituted or unsubstituted furan, substituted or unsubstitutedthiophene, substituted or unsubstituted tetrahydrofuran, substituted orunsubstituted tetrahydrothiophene, substituted or unsubstitutedbenzimidazole, substituted or unsubstituted benzoxazole, or substitutedor unsubstituted benzothiazole.

In compounds of structure II, R⁹ and R¹⁵ may be the same or differentand are selected from H, —OH, substituted or unsubstituted alkoxygroups, substituted or unsubstituted aryloxy groups, —NH₂, substitutedor unsubstituted alkylamino groups, substituted or unsubstitutedarylamino groups, substituted or unsubstituted dialkylamino groups,substituted or unsubstituted diarylamino groups, substituted orunsubstituted (alkyl)(aryl)amino groups, substituted or unsubstitutedalkyl groups, substituted or unsubstituted aryl groups, —C(═O)H,—C(═O)-alkyl groups, or —C(═O)-aryl groups. In preferred compounds ofstructure II, R⁹ is hydrogen.

In compounds of structure II, R¹⁰ is selected from substituted orunsubstituted alkyl groups, substituted or unsubstituted aryl groups,substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted heterocyclylalkyl groups, —C(═O)H, —C(═O)-alkyl groups,—C(═O)-aryl groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups,—C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups,—C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl)groups, —NH₂, —NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂ groups,—N(alkyl)(aryl) groups, —N(aryl)₂ groups, —C(═O)NH(heterocyclyl) groups,—C(═O)N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups, or—C(═O)N(aryl)(heterocyclyl) groups.

R¹¹ and R²⁰ may be the same or different in compounds of structure IIand are independently selected from substituted or unsubstituted alkylgroups, or substituted or unsubstituted aryl groups.

In compounds of structure II, R¹² is selected from H, substituted orunsubstituted alkyl groups, substituted or unsubstituted aryl groups, orsubstituted or unsubstituted heterocyclyl groups whereas R¹³ is selectedfrom H, substituted or unsubstituted alkyl groups, substituted orunsubstituted aryl groups, substituted or unsubstituted heterocyclylgroups, —OH, alkoxy groups, aryloxy groups, —NH₂, substituted orunsubstituted heterocyclylalkyl groups, substituted or unsubstitutedaminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups,substituted or unsubstituted dialkylaminoalkyl groups, substituted orunsubstituted arylaminoalkyl groups, substituted or unsubstituteddiarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkylaminogroups, substituted or unsubstituted arylamino groups, substituted orunsubstituted dialkylamino groups, substituted or unsubstituteddiarylamino groups, substituted or unsubstituted (alkyl)(aryl)aminogroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkylgroups, —C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,—C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —C(═O)-heterocyclyl groups,—C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,—C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups,—C(═O)—N(aryl)(heterocyclyl) groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkylgroups, substituted or unsubstituted alkoxyalkyl groups, substituted orunsubstituted aryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups. R¹² and R¹³ may join together to form a 5to 7 membered saturated or unsaturated, substituted or unsubstitutedN-containing ring.

In compounds of structure II, R¹⁴ is selected from H, —OH, alkoxygroups, aryloxy groups, —NH₂, —NH(alkyl) groups, —NH(aryl) groups,—N(alkyl)₂ groups, —N(aryl)₂ groups, —N(alkyl)(aryl) groups, substitutedor unsubstituted alkyl groups, substituted or unsubstituted aryl groups,—NH(heterocyclyl) groups, —N(heterocyclyl)₂ groups,—N(alkyl)(heterocyclyl) groups, or —N(aryl)(heterocyclyl) groups.

In compounds of structure II, R¹⁶ is selected from substituted orunsubstituted alkyl groups, substituted or unsubstituted aryl groups,substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted heterocyclylalkyl groups, —C(═O)H, —C(═O)-alkyl groups,—C(═O)-aryl groups, —C(═O)-heterocyclyl groups, —C(═O)NH₂,—C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups,—C═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups, —C(═O)NH-heterocyclylgroups, —C(═O)N-(heterocyclyl)₂ groups, —C(═O)N(alkyl)(heterocyclyl)groups, —C(═O)N(aryl)(heterocyclyl) groups, substituted or unsubstitutedaminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups,substituted or unsubstituted dialkylaminoalkyl groups, substituted orunsubstituted arylaminoalkyl groups, substituted or unsubstituteddiarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted or unsubstituteddiheterocyclylaminoalkyl groups, substituted or unsubstituted(heterocyclyl)(alkyl)aminoalkyl groups, substituted or unsubstituted(heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstitutedalkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups,substituted or unsubstituted hydroxyalkyl groups, or substituted orunsubstituted heterocyclyloxyalkyl groups.

In compounds of structure II, R¹⁷ is selected from H, substituted orunsubstituted alkyl groups, substituted or unsubstituted aryl groups, orsubstituted or unsubstituted heterocyclyl groups whereas R¹⁸ is selectedfrom H, substituted or unsubstituted alkyl groups, substituted orunsubstituted aryl groups, substituted or unsubstituted heterocyclylgroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)NH₂,—C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups,—C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups, —C(═O)O-alkylgroups, —C(═O)O-aryl groups, substituted or unsubstituted aminoalkylgroups, substituted or unsubstituted alkylaminoalkyl groups, substitutedor unsubstituted dialkylaminoalkyl groups, substituted or unsubstitutedarylaminoalkyl groups, substituted or unsubstituted diarylaminoalkylgroups, substituted or unsubstituted (aryl)(alkyl)aminoalkyl groups,substituted or unsubstituted heterocyclylalkyl groups,—C(═O)-heterocyclyl groups, —C(═O)—O-heterocyclyl groups,—C(═O)NH(heterocyclyl) groups, —C(═O)—N(heterocyclyl)₂ groups,—C(═O)—N(alkyl)(heterocyclyl) groups, —C(═O)—N(aryl)(heterocyclyl)groups, substituted or unsubstituted heterocyclylaminoalkyl groups,substituted and unsubstituted diheterocyclylaminoalkyl groups,substituted and unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups,substituted and unsubstituted (heterocyclyl)(aryl)aminoalkyl groups,substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups. R¹⁷ and R¹⁸ may join together to form a 5to 7 membered saturated or unsaturated, substituted or unsubstitutedN-containing ring.

Finally, in compounds of structure II, R¹⁹, R²¹, and R²² may be the sameor different and are independently selected from H, —NH₂, —NH(alkyl)groups, —NH(aryl) groups, —N(alkyl)₂ groups, —N(aryl)₂ groups,—N(alkyl)(aryl) groups, —NH(heterocyclyl) groups,—N(heterocyclyl)(alkyl) groups, —N(heterocyclyl)(aryl) groups,—N(heterocyclyl)₂ groups, substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, —OH, substituted orunsubstituted alkoxy groups, substituted or unsubstituted heterocyclylgroups, substituted or unsubstituted aryloxy groups, heterocyclyloxygroups, —NHOH, —N(alkyl)OH groups, —N(aryl)OH groups, —N(alkyl)O-alkylgroups, —N(aryl)O-alkyl groups, —N(alkyl)O-aryl groups, or—N(aryl)O-aryl groups.

Preferred compounds having the structure II include those in which R¹⁹is selected from substituted or unsubstituted alkyl groups, substitutedor unsubstituted aryl groups, —NH₂, —NH(alkyl) groups, —N(alkyl)₂groups, —NH(aryl) groups, —N(aryl)₂ groups, —N(alkyl)(aryl) groups,—NH(heterocyclyl) groups, —N(heterocyclyl)(alkyl) groups,—N(heterocyclyl)(aryl) groups, —N(heterocyclyl)₂ groups, or N-containingheterocycles, and the N-containing heterocycles are bonded to thecarbonyl carbon of the —C(═O)—R¹⁹ group through either a nitrogen atomor a carbon atom in the rings of the N-containing heterocycles. In stillmore preferred compounds in which R¹⁹ is a N-containing heterocycle, theN-containing heterocycle of the R¹⁹ group is selected from substitutedor unsubstituted morpholine, substituted or unsubstituted pyrrolidine,substituted or unsubstituted piperazine, substituted or unsubstitutedpiperidine, substituted or unsubstituted pyrrole, substituted orunsubstituted imidazole, substituted or unsubstituted pyrazole,substituted or unsubstituted 1,2,3-triazole, substituted orunsubstituted 1,2,4-triazole, substituted or unsubstituted tetrazole,substituted or unsubstituted thiomorpholine, substituted orunsubstituted homopiperazine, substituted or unsubstitutedoxazolidin-2-one, substituted or unsubstituted pyrrolidin-2-one,substituted or unsubstituted pyridine, substituted or unsubstitutedoxazole, substituted or unsubstituted isoxazole, substituted orunsubstituted thiazole, substituted or unsubstituted isothiazole,substituted or unsubstituted benzimidazole, substituted or unsubstitutedbenzoxazole, or substituted or unsubstituted benzothiazole.

Other preferred compounds having structure II are provided in which R¹⁶or R¹⁸ is selected from substituted or unsubstituted aminoalkyl groups,substituted or unsubstituted alkylaminoalkyl groups, substituted orunsubstituted arylaminoalkyl groups, substituted or unsubstituteddialkylaminoalkyl groups, substituted or unsubstituted diarylaminoalkylgroups, alkylarylaminoalkyl groups, or substituted or unsubstitutedheterocycylalkyl groups, including: —CH₂(CH₂)_(p)NH₂ groups,—CH₂(CH₂)_(p)NH(alkyl) groups, —CH₂(CH₂)_(p)NH(aryl) groups,—CH₂(CH₂)_(p)N(alkyl)₂ groups, —CH₂(CH₂)_(p)N(aryl)₂ groups,—CH₂(CH₂)_(p)N(alkyl)(aryl) groups, or —CH₂(CH₂)_(p)(heterocyclyl)groups, where p is an integer ranging from 0 to 4 and the heterocyclylgroup of the —CH₂(CH₂)_(p)(heterocyclyl) group is a N-containingheterocycle selected from substituted or unsubstituted morpholine,substituted or unsubstituted pyrrolidine, substituted or unsubstitutedpiperazine, substituted or unsubstituted piperidine, substituted orunsubstituted pyrrole, substituted or unsubstituted imidazole,substituted or unsubstituted pyrazole, substituted or unsubstituted1,2,3-triazole, substituted or unsubstituted 1,2,4-triazole, substitutedor unsubstituted tetrazole, substituted or unsubstituted thiomorpholine,substituted or unsubstituted homopiperazine, substituted orunsubstituted oxazolidin-2-one, substituted or unsubstitutedpyrrolidin-2-one, substituted or unsubstituted pyridine, substituted orunsubstituted oxazole, substituted or unsubstituted isoxazole,substituted or unsubstituted thiazole, substituted or unsubstitutedisothiazole, substituted or unsubstituted benzimidazole, substituted orunsubstituted benzoxazole, or substituted or unsubstitutedbenzothiazole.

Other particularly preferred inhibitors of VEGF-RTK are compounds havingthe structure III, tautomers of the compounds, pharmaceuticallyacceptable salts of the compounds, and pharmaceutically acceptable saltsof the tautomers. Structure III has the following formula:

In compounds of structure III, W¹, W², W³, and W⁴ are selected from C orN, and at least one of W¹, W², W³, or W⁴ is N. In some preferredcompounds of structure III, W¹ is N and R¹ is absent or H. In otherpreferred compounds of structure III, W² is N and R² is absent or H. Instill other preferred compounds of structure III, W³ is N and R³ isabsent or H. In yet other preferred compounds of structure III, W⁴ is Nand R⁴ is absent or H. In other preferred compounds of structure III,one of W¹, W², W³, and W⁴ is N whereas in other compounds of structureIII, two of W¹, W², W³, and W⁴ are N. In yet other preferredembodiments, W¹, W², and W³ are all C and W⁴ is N; W¹, W², and W⁴ areall C and W³ is N; W¹, W³, and W⁴ are all C and W² is N; or W², W³, andW⁴ are all C and W¹ is N.

In compounds of structure III, X¹, X², X³, and X⁴ are selected from C orN, and at least one of X¹, X², X³, or X⁴ is N. In some preferredcompounds of structure III, X¹ is N and R⁵ is absent or H. In otherpreferred compounds of structure III, X² is N and R⁶ is absent or H. Instill other preferred compounds of structure III, X³ is N and R⁷ isabsent or H. In yet other preferred compounds of structure III, X⁴ is Nand R⁸ is absent or H. In other preferred compounds of structure III,one of X¹, X², X³, and X⁴ is N whereas in other compounds of structureIII, two of X¹, X², X³, and X⁴ are N.

In compounds having structure III, Y is selected from H, —OH, —OR¹⁰groups, —SH, —SR¹¹ groups, —NR¹²R¹³ groups, —CN, —C(═O)—R¹⁴ groups,substituted or unsubstituted alkyl groups, substituted or unsubstitutedalkenyl groups, substituted or unsubstituted alkynyl groups, substitutedor unsubstituted aralkyl groups, substituted or unsubstitutedheterocyclylalkyl groups, substituted or unsubstituted alkylaminoalkylgroups, substituted or unsubstituted dialkylaminoalkyl groups,substituted or unsubstituted arylaminoalkyl groups, substituted orunsubstituted diarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(heterocyclyl)(alkyl)aminoalkyl groups, substituted and unsubstituted(heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstitutedheterocyclyl groups, substituted or unsubstituted aryl groups,substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups.

In preferred compounds of structure III, Y is selected from H, —OH,—OR¹⁰ groups, or —NR¹²R¹³ groups. More preferably, Y is a —NR¹²R¹³group. Still more preferably, Y is a —NR¹²R¹³ group and both R¹² and R¹³are hydrogen. In other preferred compounds having the structure III, Yis selected from —N(CH₃)₂, —NH(CH₃), —NH(CH₂CH₃), —N(CH₂CH₃)₂, —NH(aryl)groups, —N(aryl)₂ groups, —NHNH₂, —NHN(CH₃)₂, —N(CH₃)NH(CH₃),—NH(CH₂)_(m)NH₂ groups, —NH(CH₂)_(m)NH(alkyl) groups,—NH(CH₂)_(m)N(alkyl)₂ groups, —N(alkyl)(CH₂)_(m)NH₂ groups,—N(alkyl)(CH₂)_(m)NH(alkyl) groups, —N(alkyl)(CH₂)_(m)N(alkyl)₂ groups,—NH(CH₂)_(n)(heterocyclyl) groups, —N(alkyl)[(CH₂)_(n)(heterocyclyl)]groups, —NH(CH₂)_(m)OH groups, —NH(CH₂)_(m)OCH₃ groups,—NHCH₂CH(NH₂)CH(CH₃)₂, —NH(2-aminocyclohexyl), —NH(cyclohexyl), —NHOCH₃,—NH(N-morpholinyl), —NH(quinuclidyl), especially —NH(quinuclid-3-yl),and groups where R¹² and R¹³ join to form a substituted or unsubstitutedsaturated 5 or 6 membered N-containing ring, where m is 2, 3, or 4 and nis 0, 1, 2, or 3. Still more preferred compounds of this type are thosein which Y is selected from —NH(5-benzimidazolyl), —NH(CH₂)₂N(CH₃)₂,—NH(CH₂)₂OH, NH(CH₂)(4-imidazolyl), —NH(CH₂)(3-imidazolyl),—NH(CH₂)(4-pyridyl), —NH(CH₂)(2-pyridyl), —NH(CH₂)(3-pyridyl),—NH(CH₂)(2-tetrahydrofuranyl), —NH(CH₂)(4-piperidinyl),—NH(CH₂)(3-piperidinyl), —NH(CH₂)₂[2-(N-methyl-pyrrolidinyl)],—NH(CH₂)₂(2-pyrrolidinyl), —NH(CH₂)[2-(N-methylpyrrolidinyl)],—NH(CH₂)(2-pyrrolidinyl), —NH(3-piperidinyl), or —NH(3-pyrrolidinyl).

In compounds of structure III, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ may bethe same or different and are independently selected from H, Cl, Br, F,I, —NO₂, —CN, —OH, —OR¹⁵ groups, —NR¹⁶R¹⁷ groups, —C(═O)R¹⁸ groups, —SH,—SR¹⁹ groups, —S(═O)R²⁰ groups, S(═O)₂R²¹ groups, substituted orunsubstituted amidinyl groups, substituted or unsubstituted guanidinylgroups, substituted or unsubstituted primary, secondary, or tertiaryalkyl groups, substituted or unsubstituted aryl groups, substituted orunsubstituted alkenyl groups, substituted or unsubstituted alkynylgroups, substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted alkylaminoalkyl groups, substituted or unsubstituteddialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkylgroups, substituted or unsubstituted diarylaminoalkyl groups,substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substitutedor unsubstituted heterocyclylalkyl groups, substituted or unsubstitutedaminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkylgroups, substituted and unsubstituted diheterocyclylaminoalkyl groups,substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups,substituted and unsubstituted (aryl)(heterocyclyl)aminoalkyl groups,substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups, and R¹ is absent or H if W¹ is N, R² isabsent or H if W² is N, R³ is absent or H if W³ is N, R⁴ is absent or Hif W⁴ is N, R⁵ is absent or H if X¹ is N, R⁶ is absent or H if X² is N,R⁷ is absent or H if X³ is N, and R⁸ is absent or H if X⁴ is N.

Some preferred compounds have the structure III where at least one ofR¹, R², R³, R⁴, R⁵, R⁶, R⁷, or R⁸ is a substituted or unsubstitutedheterocyclyl group selected from a group of heterocycles that includesmorpholine, piperazine, piperidine, 1,2,3-triazole, 1,2,4-triazole,tetrazole, pyrrolidine, pyrazole, pyrrole, thiomorpholine,homopiperazine, benzimidazole, oxazolidin-2-one, pyrrolidin-2-one,imidazole, isothiazole, thiazole, thiophene, furan, pyran,tetrahydrothiophene, tetrahydrofuran, tetrahydropyran, and pyridine.

Still other preferred compounds having structure III are those in whichR¹, R², and R³ are H, and W⁴ is N. Still other compounds having theformula of structure III are provided in which R², R³, and R⁴ are H, andW¹ is N. Still other compounds having the formula of structure III areprovided in which R¹, R³, and R⁴ are H, and W² is N. Still othercompounds having the formula of structure III are provided in which R¹,R², and R⁴ are H, and W³ is N.

In other preferred compounds, R¹ or R² is selected from F, Cl,substituted or unsubstituted alkoxy groups, substituted or unsubstitutedheterocyclyloxy groups, substituted or unsubstituted heterocyclylalkoxygroups, substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted alkyl-, heterocycyl-, or aryl-aminoalkyl groups,substituted or unsubstituted dialkyl- or diaryl-aminoalkyl groups,substituted or unsubstituted alkylarylaminoalkyl groups, substituted orunsubstituted alkyl- and aryl-aminoalkoxy groups, substituted orunsubstituted dialkyl- and diaryl-aminoalkoxy groups, or substituted orunsubstituted alkylarylaminoalkoxy groups. Particular examples include:—C(═O)N(alkyl)₂ groups, —OCH₂CH₂(N-morpholinyl), N-morpholinyl,—OCH₂CH₂N(alkyl)₂ groups, —OCH₂CH₂NH(alkyl) groups, —OCH₂CH₂NH₂,—OCH₂CH₂NH(aryl) groups, —OCH₂CH₂N(aryl)₂ groups, alkoxy groups,—OCH₂CH₂N(alkyl)(aryl) groups, —O(4-piperidinyl),—O[4-(1-alkyl)piperidinyl] groups, —OCH₂(2-pyridyl), —O(3-pyrrolidinyl),or —O[3-(1-alkyl)pyrrolidinyl] groups.

Still other preferred compounds include those in which R² is selectedfrom F, Cl, —NO₂, substituted or unsubstituted alkoxy groups,substituted or unsubstituted heterocyclylalkoxy groups, substituted orunsubstituted heterocyclyl groups, substituted or unsubstituted alkyl-,heterocycyl-, or aryl-aminoalkyl groups, substituted or unsubstituteddialkyl- and diaryl-aminoalkyl groups, substituted or unsubstitutedalkylarylaminoalkyl groups, substituted or unsubstituted alkyl- andaryl-aminoalkoxy groups, substituted or unsubstituted dialkyl- anddiaryl-aminoalkoxy groups, substituted or unsubstitutedalkylarylaminoalkoxy groups. Particular examples include: —OCH₃,N-morpholinyl, —N-cis-dialkylmorpholinyl, —N-(4-alkyl)piperazinyl, or—OCH₂(2-pyridyl).

In yet preferred compounds having structure III, R⁵, R⁶, and R⁷ arehydrogen, and X⁴ is N. In still other more preferred compounds ofstructure III, R⁶, R⁷ or both R⁶ and R⁷ are alkyl groups having from oneto four carbon atoms. In yet other preferred compounds of structure III,R⁶ or R⁷ is an —OR¹⁵ group and R¹⁵ is an alkyl, aryl, heterocyclyl, orheterocyclylalkyl group. In still further preferred compounds ofstructure III, R⁶ or R⁷ is a —OCH₂(CH₂)_(q)(heterocyclyl) group and q is0, 1, 2, 3, or 4. In more preferred compounds in which R⁶ or R⁷ is a—OCH₂(CH₂)_(q)-(heterocyclyl) group, the heterocyclyl group of the—OCH₂(CH₂)_(n)(heterocyclyl) group is a heterocycle selected fromsubstituted or unsubstituted morpholine, substituted or unsubstitutedpiperazine, substituted or unsubstituted piperidine, substituted orunsubstituted pyrrolidine, substituted or unsubstituted pyrrole,substituted or unsubstituted imidazole, substituted or unsubstitutedpyrazole, substituted or unsubstituted 1,2,3-triazole, substituted orunsubstituted 1,2,4-triazole, substituted or unsubstituted tetrazole,substituted or unsubstituted thiomorpholine, substituted orunsubstituted homopiperazine, substituted or unsubstitutedoxazolidin-2-one, substituted or unsubstituted pyrrolidin-2-one,substituted or unsubstituted pyridine, substituted or unsubstitutedoxazole, substituted or unsubstituted isoxazole, substituted orunsubstituted thiazole, substituted or unsubstituted isothiazole,substituted or unsubstituted furan, substituted or unsubstitutedthiophene, substituted or unsubstituted tetrahydrofuran, substituted orunsubstituted tetrahydrothiophene, substituted or unsubstitutedbenzimidazole, substituted or unsubstituted benzoxazole, or substitutedor unsubstituted benzothiazole.

In compounds of structure III, R⁹ is selected from H, —OH, substitutedor unsubstituted alkoxy groups, substituted or unsubstituted aryloxygroups, —NH₂, substituted or unsubstituted alkylamino groups,substituted or unsubstituted arylamino groups, substituted orunsubstituted dialkylamino groups, substituted or unsubstituteddiarylamino groups, substituted or unsubstituted (alkyl)(aryl)aminogroups, substituted or unsubstituted alkyl groups, substituted orunsubstituted aryl groups, —C(═O)H, —C(═O)-alkyl groups, or —C(═O)-arylgroups. One group of particularly preferred compounds of structure IIIare those in which R⁹ is hydrogen.

In compounds of structure III, R¹⁰ is selected from substituted orunsubstituted alkyl groups, substituted or unsubstituted aryl groups,substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted heterocyclylalkyl groups, —C(═O)H, —C(═O)-alkyl groups,—C(═O)-aryl groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups,—C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups,—C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl)groups, —NH₂, —NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂ groups,—N(alkyl)(aryl) groups, —N(aryl)₂ groups, —C(═O)NH(heterocyclyl) groups,—C(═O)N(heterocyclyl)₂ groups, —C(═O)N(alkyl)(heterocyclyl) groups, or—C(═O)N(aryl)(heterocyclyl) groups;

In compounds of structure III, R¹¹ and R¹⁹ may be the same or differentand are independently selected from substituted or unsubstituted alkylgroups, or substituted or unsubstituted aryl groups whereas R¹² isselected from H, substituted or unsubstituted alkyl groups, substitutedor unsubstituted aryl groups, or substituted or unsubstitutedheterocyclyl groups.

In compounds of structure III, R¹³ is selected from H, substituted orunsubstituted alkyl groups, substituted or unsubstituted aryl groups,substituted or unsubstituted heterocyclyl groups, —OH, alkoxy groups,aryloxy groups, —NH₂, substituted or unsubstituted heterocyclylalkylgroups, substituted or unsubstituted aminoalkyl groups, substituted orunsubstituted alkylaminoalkyl groups, substituted or unsubstituteddialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkylgroups, substituted or unsubstituted diarylaminoalkyl groups,substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substitutedor unsubstituted alkylamino groups, substituted or unsubstitutedarylamino groups, substituted or unsubstituted dialkylamino groups,substituted or unsubstituted diarylamino groups, substituted orunsubstituted (alkyl)(aryl)amino groups, —C(═O)H, —C(═O)-alkyl groups,—C(═O)-aryl groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups,—C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups,—C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl)groups, —C(═O)-heterocyclyl groups, —C(═O)—O-heterocyclyl groups,—C(═O)NH(heterocyclyl) groups, —C(═O)—N(heterocyclyl)₂ groups,—C(═O)—N(alkyl)(heterocyclyl) groups, —C(═O)—N(aryl)(heterocyclyl)groups, substituted or unsubstituted heterocyclylaminoalkyl groups,substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups. R¹² and R¹³ may join together to form a 5to 7 membered saturated or unsaturated, substituted or unsubstitutedN-containing ring.

In compounds of structure III, R¹⁴ is selected from H, —OH, alkoxygroups, aryloxy groups, —NH₂, —NH(alkyl) groups, —NH(aryl) groups,—N(alkyl)₂ groups, —N(aryl)₂ groups, —N(alkyl)(aryl) groups, substitutedor unsubstituted alkyl groups, substituted or unsubstituted aryl groups,—NH(heterocyclyl) groups, —N(heterocyclyl)₂ groups,—N(alkyl)(heterocyclyl) groups, or —N(aryl)(heterocyclyl) groups.

In compounds of structure III, R¹⁵ is selected from substituted orunsubstituted alkyl groups, substituted or unsubstituted aryl groups,substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted heterocyclylalkyl groups, —C(═O)H, —C(═O)-alkyl groups,—C(═O)-aryl groups, —C(═O)-heterocyclyl groups, —C(═O)NH₂,—C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups,—C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups,—C(═O)NH-heterocyclyl groups, —C(═O)N-(heterocyclyl)₂ groups,—C(═O)N(alkyl)(heterocyclyl) groups, —C(═O)N(aryl)(heterocyclyl) groups,substituted or unsubstituted aminoalkyl groups, substituted orunsubstituted alkylaminoalkyl groups, substituted or unsubstituteddialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkylgroups, substituted or unsubstituted diarylaminoalkyl groups,substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substitutedor unsubstituted heterocyclylaminoalkyl groups, substituted orunsubstituted diheterocyclylaminoalkyl groups, substituted orunsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted orunsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, substituted or unsubstituted hydroxyalkyl groups,or substituted or unsubstituted heterocyclyloxyalkyl groups.

In compounds of structure III, R¹⁶ is selected from H, substituted orunsubstituted alkyl groups, substituted or unsubstituted aryl groups, orsubstituted or unsubstituted heterocyclyl groups whereas R¹⁷ is selectedfrom H, substituted or unsubstituted alkyl groups, substituted orunsubstituted aryl groups, substituted or unsubstituted heterocyclylgroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)NH₂,—C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups,—C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups, —C(═O)O-alkylgroups, —C(═O)O-aryl groups, substituted or unsubstituted aminoalkylgroups, substituted or unsubstituted alkylaminoalkyl groups, substitutedor unsubstituted dialkylaminoalkyl groups, substituted or unsubstitutedarylaminoalkyl groups, substituted or unsubstituted diarylaminoalkylgroups, substituted or unsubstituted (aryl)(alkyl)aminoalkyl groups,substituted or unsubstituted heterocyclylalkyl groups,—C(═O)-heterocyclyl groups, —C(═O)—O-heterocyclyl groups,—C(═O)NH(heterocyclyl) groups, —C(═O)—N(heterocyclyl)₂ groups,—C(═O)—N(alkyl)(heterocyclyl) groups, —C(═O)—N(aryl)(heterocyclyl)groups, substituted or unsubstituted heterocyclylaminoalkyl groups,substituted and unsubstituted diheterocyclylaminoalkyl groups,substituted and unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups,substituted and unsubstituted (heterocyclyl)(aryl)aminoalkyl groups,substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups. R¹⁶ and R¹⁷ may join together to form a 5to 7 membered saturated or unsaturated, substituted or unsubstitutedN-containing ring.

Finally, in compounds of structure III, R¹⁸, R²⁰, and R²¹ may be thesame or different and are independently selected H, —NH₂, —NH(alkyl)groups, —NH(aryl) groups, —N(alkyl)₂ groups, —N(aryl)₂ groups,—N(alkyl)(aryl) groups, —NH(heterocyclyl) groups,—N(heterocyclyl)(alkyl) groups, —N(heterocyclyl)(aryl) groups,—N(heterocyclyl)₂ groups, substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, —OH, substituted orunsubstituted alkoxy groups, substituted or unsubstituted heterocyclylgroups, substituted or unsubstituted aryloxy groups, heterocyclyloxygroups, —NHOH, —N(alkyl)OH groups, —N(aryl)OH groups, —N(alkyl)O-alkylgroups, —N(aryl)O-alkyl groups, —N(alkyl)O-aryl groups, or—N(aryl)O-aryl groups.

Preferred compounds having the structure III include those in which R¹⁸is selected from substituted or unsubstituted alkyl groups, substitutedor unsubstituted aryl groups, —NH₂, —NH(alkyl) groups, —N(alkyl)₂groups, —NH(aryl) groups, —N(aryl)₂ groups, —N(alkyl)(aryl) groups,—NH(heterocyclyl) groups, —N(heterocyclyl)(alkyl) groups,—N(heterocyclyl)(aryl) groups, —N(heterocyclyl)₂ groups, or N-containingheterocycles, and the N-containing heterocycles are bonded to thecarbonyl carbon of the —C(═O)—R¹⁸ group through either a nitrogen atomor a carbon atom in the rings of the N-containing heterocycles. In stillmore preferred compounds in which R¹⁸ is a N-containing heterocycle, theN-containing heterocycle of the R¹⁸ group is selected from substitutedor unsubstituted morpholine, substituted or unsubstituted pyrrolidine,substituted or unsubstituted piperazine, substituted or unsubstitutedpiperidine, substituted or unsubstituted pyrrole, substituted orunsubstituted imidazole, substituted or unsubstituted pyrazole,substituted or unsubstituted 1,2,3-triazole, substituted orunsubstituted 1,2,4-triazole, substituted or unsubstituted tetrazole,substituted or unsubstituted thiomorpholine, substituted orunsubstituted homopiperazine, substituted or unsubstitutedoxazolidin-2-one, substituted or unsubstituted pyrrolidin-2-one,substituted or unsubstituted pyridine, substituted or unsubstitutedoxazole, substituted or unsubstituted isoxazole, substituted orunsubstituted thiazole, substituted or unsubstituted isothiazole,substituted or unsubstituted benzimidazole, substituted or unsubstitutedbenzoxazole, or substituted or unsubstituted benzothiazole.

Other preferred compounds having structure III are provided in which R¹⁵or R¹⁷ is selected from substituted or unsubstituted aminoalkyl groups,substituted or unsubstituted alkylaminoalkyl groups, substituted orunsubstituted arylaminoalkyl groups, substituted or unsubstituteddialkylaminoalkyl groups, substituted or unsubstituted diarylaminoalkylgroups, alkylarylaminoalkyl groups, or substituted or unsubstitutedheterocycylalkyl groups, including: —CH₂(CH₂)_(p)NH₂ groups,—CH₂(CH₂)_(p)NH(alkyl) groups, —CH₂(CH₂)_(p)NH(aryl) groups,—CH₂(CH₂)_(p)N(alkyl)₂ groups, —CH₂(CH₂)_(p)N(aryl)₂ groups,—CH₂(CH₂)_(p)N(alkyl)(aryl) groups, or —CH₂(CH₂)_(p)(heterocyclyl)groups, where p is an integer ranging from 0 to 4 and the heterocyclylgroup of the —CH₂(CH₂)_(p)(heterocyclyl) group is a N-containingheterocycle selected from substituted or unsubstituted morpholine,substituted or unsubstituted pyrrolidine, substituted or unsubstitutedpiperazine, substituted or unsubstituted piperidine, substituted orunsubstituted pyrrole, substituted or unsubstituted imidazole,substituted or unsubstituted pyrazole, substituted or unsubstituted1,2,3-triazole, substituted or unsubstituted 1,2,4-triazole, substitutedor unsubstituted tetrazole, substituted or unsubstituted thiomorpholine,substituted or unsubstituted homopiperazine, substituted orunsubstituted oxazolidin-2-one, substituted or unsubstitutedpyrrolidin-2-one, substituted or unsubstituted pyridine, substituted orunsubstituted oxazole, substituted or unsubstituted isoxazole,substituted or unsubstituted thiazole, substituted or unsubstitutedisothiazole, substituted or unsubstituted benzimidazole, substituted orunsubstituted benzoxazole, or substituted or unsubstitutedbenzothiazole.

Compounds of structure I and structure II may be synthesized from simplestarting molecules as shown in Schemes 1-3 and exemplified in theExamples. As shown in Scheme 1, compounds of structure I and II maygenerally be prepared using pyridines or other heterocycles substitutedwith amines and carboxylic acid groups.

As shown in Scheme 1, a substituted pyridine such as a substituted orunsubstituted 3-amino-pyridine-4-carboxylic acid may be reacted with anacyl halide such as methyl 2-(chlorocarbonyl)acetate to produce an amidethat will react with a substituted or unsubstituted 1,2-diaminobenzene.The resulting product is a 4-hydroxy-substituted compound of structure Ior II. The use of starting pyridines with different substitutionpatterns such as 2-aminonicotinic acid (2-aminopyridine-4-carboxylicacid) provides compounds where the nitrogen is in a different positionin the pyridine ring of the final compound. One skilled in the art willrecognize that the procedure set forth in Scheme 1 may be modified toproduce various compounds.

A method for preparing 4-amino substituted compounds of structures I andII is shown in Scheme 2.

As shown in Scheme 2, pyridines and other heterocycles substituted withamine and nitrile groups may be used to synthesize 4-amino substitutedcompounds of Structure I and II. A compound such as ethyl 2-cyanoacetatemay be reacted with ethanol to produce ethyl 3-ethoxy-3-iminopropanoatehydrochloride. Subsequent reaction with a substituted or unsubstituted1,2-phenylenediamine provides substituted or unsubstituted ethyl2-benzimidazol-2-ylacetate. Reaction of a substituted or unsubstitutedethyl 3 benzimidazol-2-ylacetate with a pyridine having an amine andnitrile group such as substituted or unsubstituted3-amino-4-cyanopyridine with a base such as lithiumbis(trimethylsilyl)amide or a Lewis acid such as tin tetrachlorideprovides the substituted or unsubstituted 4-amino substituted compoundof structure I and II.

Scheme 3 illustrates a general synthetic route that allows for thesynthesis of 4-dialkylamino and 4-alkylamino compounds of structures Iand II. An inspection of Scheme 3 shows that 4-hydroxy substitutedcompounds of structure I or II may be converted into the 4-chloroderivative by reaction with phosphorous oxychloride. The 4-chloroderivative may then be reacted with an alkylamine or dialkylamine toproduce the corresponding 4-alkylamino or 4-dialkylamino derivative.Deprotection affords the final 4-alkylamino or 4-dialkylamino compoundsof structure I and II. Other groups that may be reacted with the4-chloro derivative in this manner include, but are not limited to, ROH,RSH, and CuCN.

Heteroaromatic diamines may be used as precursors of compounds ofstructure III. The synthesis of compounds of structure III where Y═NH₂is depicted in Scheme 4.

A compound such as ethyl cyanoacetate may be condensed with asubstituted or unsubstituted heterocycle containing two ortho aminogroups such as a substituted or unsubstituted 1,2-diaminopyridine toobtain a substituted or unsubstituted2-imidazolo[5,4-b]pyridin-2-ylethanenitrile, which may be hydrolyzed inacidic medium to provide a substituted or unsubstituted ethyl2-imidazolo[5,4-b]pyridin-2-ylacetate. As an alternate route, asubstituted or unsubstituted ethyl 2-imidazolo[5,4-b]pyridin-2-ylacetatemay be obtained from a compound such as the hydrochloride salt of3-ethoxy-3-iminopropanoate and a substituted or unsubtituted1,2-diaminopyridine. Reaction of a substituted or unsubstituted ethyl2-imidazolo[5,4-b]pyridin-2-ylacetates with a pyridine having an amineand nitrile group such as a substituted or unsubstituted3-amino-4-cyanopyridine and a base such as lithiumbis(trimethylsilyl)amide provides the substituted or unsubstitutedcompound of structure III.

Scheme 5 illustrates just a few of the methods that may be used toproduce a variety of 2-amino anilines. Halo (X=halogen) nitroanilinesmay be reacted with a wide variety of nucleophiles (Nu⁻) such asalcohols and amines to produce functionalized nitroanilines which maysubsequently be reduced to diamines. The alcohol moiety of a nitroaminophenol may be modified using known methods to introduce a broad range ofsubstituents into a diamine for subsequent inclusion in compound of theinvention.

The instant invention also provides for compositions which may beprepared by mixing one or more compounds of the instant invention, orpharmaceutically acceptable salts or tautomers thereof, withpharmaceutically acceptable carriers, excipients, binders, diluents orthe like to treat or ameliorate a variety of disorders related to theactivity of VEGF-RTK, more particularly angiogenesis associated withcancer. Such compositions can be in the form of, for example, granules,powders, tablets, capsules, syrup, suppositories, injections, emulsions,elixirs, suspensions or solutions. The instant compositions can beformulated for various routes of administration, for example, by oraladministration, by nasal administration, by rectal administration,subcutaneous injection, intravenous injection, intramuscular injections,or intraperitoneal injection. The following dosage forms are given byway of example and should not be construed as limiting the instantinvention.

For oral, buccal, and sublingual administration, powders, suspensions,granules, tablets, pills, capsules, gelcaps, and caplets are acceptableas solid dosage forms. These can be prepared, for example, by mixing oneor more compounds of the instant invention, or pharmaceuticallyacceptable salts or tautomers thereof, with at least one additive suchas a starch or other additive. Suitable additives are sucrose, lactose,cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates,chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins,collagens, casein, albumin, synthetic or semi-synthetic polymers orglycerides. Optionally, oral dosage forms can contain other ingredientsto aid in administration, such as an inactive diluent, or lubricantssuch as magnesium stearate, or preservatives such as paraben or sorbicacid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, adisintegrating agent, binders, thickeners, buffers, sweeteners,flavoring agents or perfuming agents. Tablets and pills may be furthertreated with suitable coating materials known in the art.

Liquid dosage forms for oral administration may be in the form ofpharmaceutically acceptable emulsions, syrups, elixirs, suspensions, andsolutions, which may contain an inactive diluent, such as water.Pharmaceutical formulations may be prepared as liquid suspensions orsolutions using a sterile liquid, such as, but not limited to, an oil,water, an alcohol, and combinations of these. Pharmaceutically suitablesurfactants, suspending agents, emulsifying agents, may be added fororal or parenteral administration.

As noted above, suspensions may include oils. Such oil include, but arenot limited to, peanut oil, sesame oil, cottonseed oil, corn oil andolive oil. Suspension preparation may also contain esters of fatty acidssuch as ethyl oleate, isopropyl myristate, fatty acid glycerides andacetylated fatty acid glycerides. Suspension formulations may includealcohols, such as, but not limited to, ethanol, isopropyl alcohol,hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as butnot limited to, poly(ethyleneglycol), petroleum hydrocarbons such asmineral oil and petrolatum; and water may also be used in suspensionformulations.

For nasal administration, the pharmaceutical formulations may be a sprayor aerosol containing and appropriate solvents and optionally othercompounds such as, but not limited to, stabilizers, antimicrobialagents, antioxidants, pH modifiers, surfactants, bioavailabilitymodifiers and combinations of these. A propellant for an aerosolformulation may include compressed air, nitrogen, carbon dioxide, or ahydrocarbon based low boiling solvent.

Injectable dosage forms generally include aqueous suspensions or oilsuspensions which may be prepared using a suitable dispersant or wettingagent and a suspending agent. Injectable forms may be in solution phaseor in the form of a suspension, which is prepared with a solvent ordiluent. Acceptable solvents or vehicles include sterilized water,Ringer's solution, or an isotonic aqueous saline solution.Alternatively, sterile oils may be employed as solvents or suspendingagents. Preferably, the oil or fatty acid is non-volatile, includingnatural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

For injection, the pharmaceutical formulation may be a powder suitablefor reconstitution with an appropriate solution as described above.Examples of these include, but are not limited to, freeze dried, rotarydried or spray dried powders, amorphous powders, granules, precipitates,or particulates. For injection, the formulations may optionally containstabilizers, pH modifiers, surfactants, bioavailability modifiers andcombinations of these.

For rectal administration, the pharmaceutical formulations may be in theform of a suppository, an ointment, an enema, a tablet or a cream forrelease of compound in the intestines, sigmoid flexure and/or rectum.Rectal suppositories are prepared by mixing one or more compounds of theinstant invention, or pharmaceutically acceptable salts or tautomers ofthe compound, with acceptable vehicles, for example, cocoa butter orpolyethylene glycol, which is present in a solid phase at normal storingtemperatures, and present in a liquid phase at those temperaturessuitable to release a drug inside the body, such as in the rectum. Oilsmay also be employed in the preparation of formulations of the softgelatin type and suppositories. Water, saline, aqueous dextrose andrelated sugar solutions, and glycerols may be employed in thepreparation of suspension formulations which may also contain suspendingagents such as pectins, carbomers, methyl cellulose, hydroxypropylcellulose or carboxymethyl cellulose, as well as buffers andpreservatives.

Besides those representative dosage forms described above,pharmaceutically acceptable excipients and carries are generally knownto those skilled in the art and are thus included in the instantinvention. Such excipients and carriers are described, for example, in“Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991),which is incorporated herein by reference.

The formulations of the invention may be designed for to beshort-acting, fast-releasing, long-acting, and sustained-releasing asdescribed below. Thus, the pharmaceutical formulations may also beformulated for controlled release or for slow release.

The instant compositions may also comprise, for example, micelles orliposomes, or some other encapsulated form, or may be administered in anextended release form to provide a prolonged storage and/or deliveryeffect. Therefore, the pharmaceutical formulations may be compressedinto pellets or cylinders and implanted intramuscularly orsubcutaneously as depot injections or as implants such as stents. Suchimplants may employ known inert materials such as silicones andbiodegradable polymers.

Specific dosages may be adjusted depending on conditions of disease, theage, body weight, general health conditions, sex, and diet of thesubject, dose intervals, administration routes, excretion rate, andcombinations of drugs. Any of the above dosage forms containingeffective amounts are well within the bounds of routine experimentationand therefore, well within the scope of the instant invention.

A therapeutically effective dose may vary depending upon the route ofadministration and dosage form. The preferred compound or compounds ofthe instant invention is a formulation that exhibits a high therapeuticindex. The therapeutic index is the dose ratio between toxic andtherapeutic effects which can be expressed as the ratio between LD₅₀ andED₅₀. The LD₅₀ is the dose lethal to 50% of the population and the ED₅₀is the dose therapeutically effective in 50% of the population. The LD₅₀and ED₅₀ are determined by standard pharmaceutical procedures in animalcell cultures or experimental animals.

“Treating” within the context of the instant invention, means analleviation of symptoms associated with a disorder or disease, or haltof further progression or worsening of those symptoms, or prevention orprophylaxis of the disease or disorder. For example, within the contextof treating patients in need of an inhibitor of VEGF-RTK, successfultreatment may include a reduction in the proliferation of capillariesfeeding a tumor or diseased tissue, an alleviation of symptoms relatedto a cancerous growth or tumor, proliferation of capillaries, ordiseased tissue, a halting in capillary proliferation, or a halting inthe progression of a disease such as cancer or in the growth ofcancerous cells. Treatment may also include administering thepharmaceutical formulations of the present invention in combination withother therapies. For example, the compounds and pharmaceuticalformulations of the present invention may be administered before,during, or after surgical procedure and/or radiation therapy. Thecompounds of the invention can also be administered in conjunction withother anti-cancer drugs including those used in antisense and genetherapy. Examples of standard chemotherapeutic agents that the compoundsof the present may be used with include, but are not limited to,cisplatin, taxol, and 5-fluorouracil.

Pharmaceutical formulations according to the invention include any ofthe compounds described above in combination with a pharmaceuticallyacceptable carrier.

A method of treating a patient in need of an inhibitor of vascularendothelial growth factor receptor tyrosine kinase includesadministering an effective amount of a pharmaceutical formulationaccording to the invention to a patient in need thereof.

A method for inhibiting tumor growth in a patient includes administeringan effective amount of the compound or a pharmaceutically acceptablesalt thereof to a patient having a tumor.

A method for inhibiting the proliferation of capillaries in a patientincludes administering an effective amount of the compound or apharmaceutically acceptable salt thereof according to a patient in need.

A method of preparing pharmaceutical formulations includes mixing any ofthe above-described compounds with a pharmaceutically acceptable carrierand water or an aqueous solution.

The present invention, thus generally described, will be understood morereadily by reference to the following examples, which are provided byway of illustration and are not intended to be limiting of the presentinvention.

EXAMPLES

The following abbreviations are used throughout the Examples:

ATP: Adenosine triphosphate BSA: Bovine Serum Albumin DMSO:Dimethylsulfoxide DTT: DL-Dithiothreitol EDTA: Ethylene diaminetetraacetic acid EtOAc: Ethyl acetate EtOH: Ethanol HBTU:O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphateIC₅₀ value: The concentration of an inhibitor that causes a 50 percentreduction in a measured activity LiHMDS: Lithiumbis(trimethylsilyl)amide MeOH: Methanol NaOH: Sodium hydroxide NaOMe:Sodium methoxide NMP: N-methylpyrrolidone TFA: Trifluoroacetic acid THF:Tetrahydrofuran

Various functionalized aryl diamines were obtained from commercialsources, prepared by methods know to those of skilled in the art, orwere prepared by the following general methods. The compounds were namedusing Nomenclator (v. 3.0 & v. 5.0) from CmemInovation Software, Inc.and ACD/Name v. 4.53.

The various aryl diamine starting materials used to synthesizebenzimidazole acetates may be obtained from commercial sources, preparedby methods know to one of skill in the art, or prepared by the followinggeneral methods 1-7.

2,4-Difluoronitrobenzene (1.0 eq) was placed in a dry round-bottomedflask equipped with a dry ice condenser charged with acetone and dryice. Ammonia was condensed into the flask and the resulting solution wasstirred at reflux for 7 hours. A yellow precipitate formed within 1hour. After 7 hours, the condenser was removed and the liquid ammoniawas allowed to evaporate over several hours. The crude product waspurified by flash chromatography on silica gel (85:15 hexanes:ethylacetate, product at R_(f)=0.32, contaminant at R_(f)=0.51); GC/MS m/z156.1 (M+), R_(t) 11.16 minutes.

The resulting 5-fluoro-2-nitrophenylamine (1.0 eq) and an amine (1.1 eq)e.g. N-methyl piperazine, were dissolved in NMP and triethylamine (2.0eq) was added. The reaction mixture was heated at 100° C. for 3 hours.The solution was then cooled to room temperature and diluted with water.The resulting precipitate was filtered and dried under vacuum to providethe 2-nitro-diamino product. Alternatively, the same product may beobtained from commercially available 5-chloro-2-nitrophenylamine underidentical conditions except heating at 130° C. for 1-2 days. In someexamples, the displacement on either 5-fluoro-2-nitrophenylamine or5-chloro-2-nitrophenylamine can be conducted in neat amine (5 eq) at100° C. or 130° C., respectively. The product is isolated in anidentical manner. LC/MS m/z 237.1 (MH+), R_(t) 1.304 minutes.

The nitroamine (1.0 eq) and 10% Pd/C (0.1 eq) was suspended in anhydrousethanol at room temperature. The reaction flask was evacuated andsubsequently filled with H₂. The resulting mixture was then stirredunder a hydrogen atmosphere overnight. The resulting solution wasfiltered through Celite and concentrated under vacuum to provide thecrude product which was used without further purification.

A round-bottom flask was charged with 2,3-difluoro-6-nitrophenylamine (1eq) and enough NMP to make a viscous slurry. An amine (5 eq), e.g.N-methyl piperazine, was added and the solution was heated at 100° C.After 2 hours, the solution was cooled and poured into water. A brightyellow solid formed which was filtered and dried. The nitroamine wasreduced as in Method 1 to provide the crude product which was usedwithout further purification. LC/MS m/z 225.1 (MH+), R_(t) 0.335minutes.

To a 0.1 M DMF solution of 1,3-difluoro-2-nitrobenzene was added Et₃N (2eq) followed by an amine (1 eq), e.g. morpholine. The mixture wasstirred for 18 hours and then diluted with water and extracted withethyl acetate. LC/MS m/z 227.2 (MH+), R_(t) 2.522 minutes. The combinedorganic layers were dried over MgSO₄, filtered, and concentrated.Ammonia was condensed into a bomb containing the crude product. The bombwas sealed and heated to 100° C. (over 400 psi). After 72 hours the bombwas allowed to cool and the ammonia was evaporated to provide a reddishsolid. The nitroamine was reduced as in Method 1 to provide the crudeproduct which was used without further purification. LC/MS m/z 194.1(MH+), R_(t) 1.199 minutes.

To a stirred NMP solution containing NaH (1.3 eq) was added an alcohol(1.0 eq), e.g. 2-methyloxyethanol. The resulting mixture was thenstirred for 30 minutes. A slurry of 5-fluoro-2-nitrophenylamine in NMPwas then added slowly. The mixture was then heated to 100° C. After 2hours, the reaction mixture was cooled and water was added. The mixturewas then filtered and the captured solid was washed with water andpurified by silica gel chromatography (1:1 ethyl acetate:hexane). LC/MSm/z 213.2 (MH+), R_(t) 2.24 minutes. The nitroamine was reduced as inMethod 1 to provide the crude product which was used without furtherpurification. LC/MS M/z 183.1 (MH+), R_(t) 0.984 minutes.

Diisopropyl azodicarboxylate (1.1 eq) was added dropwise to a stirredsolution of 4-amino-3-nitrophenol (1.0 eq), triphenylphosphine (1.1 eq),and an alcohol, e.g. N-(2-hydroxyethyl)morpholine (1.0 eq), intetrahydrofuran at 0° C. The mixture was allowed to warm to roomtemperature and stirred for 18 hours. The solvent was evaporated, andthe product was purified by silica gel chromatography (98:2CH₂Cl₂:methanol) to yield 4-(2-morpholin-4-ylethoxy)-2-nitrophenylamineas a dark reddish-brown oil. LC/MS m/z 268. 0 (MH+), R_(t) 1.01 minutes.The nitroamine was reduced as in Method 1 to give the crude productwhich was used without further purification. LC/MS m/z 238.3 (MH+),R_(t) 0.295 minutes.

To a flask charged with 4-amino-3-nitrophenol (1 eq), K₂CO₃ (2 eq), and2-butanone was added an alkyl dibromide, e.g. 1,3-dibromopropane (1.5eq). The resulting mixture was then heated at 80° C. for 18 hours. Aftercooling, the mixture was filtered, concentrated, and diluted with water.The solution was then extracted with CH₂Cl₂ (3×) and the combinedorganic layers were concentrated to give a solid that was then washedwith pentane. LCMS m/z 275.1 (MH+), R_(t) 2.74 minutes.

An acetonitrile solution of the bromide prepared above, an amine, e.g.pyrrolidine (5 eq), CS₂CO₃ (2 eq) and Bu₄NI (0.1 eq) was heated at 70°C. for 48 hours. The reaction mixture was cooled, filtered, andconcentrated. The residue was dissolved in CH₂Cl₂, washed with water,and concentrated to give the desired nitroamine,2-nitro-4-(3-pyrrolidin-1-ylpropoxy)phenylamine. LCMS m/z 266.2 (MH+),R_(t) 1.51 minutes. The nitroamine was reduced as in Method 1 to providethe crude product which was used without further purification.

To a suspension of 6-chloro-3-nitropyridin-2-amine (1 eq) inacetonitrile was added an amine, e.g. morpholine (4 eq). The resultingreaction mixture was stirred at 70° C. for 5 hours. The solvent wasevaporated under reduced pressure, and the residue triturated with etherto provide the desired compound as a bright yellow powder. LC/MS m/z225.0 (MH+), R_(t) 1.79 minutes. The nitroamine was reduced as in Method1 to provide the crude product which was used without furtherpurification.

Example 1

3-[2-(Methoxycarbonyl)acetylamino]pyridine-4-carboxylic acid

A solution of 3-aminopyridine-4-carboxylic acid (1.0 eq), methyl2-(chlorocarbonyl)acetate (1.1 eq), and triethylamine (2.0 eq) inacetone was stirred overnight at room temperature. The solvent wasremoved in vacuo. The product was used without further purification.LC/MS m/z 239.2 (MH+), R_(t) 1.40 minutes.

3-Benzimidazol-2-yl-4-hydroxyhydropyridino[3,4-b]pyridin-2-one

3-[2-(Methoxycarbonyl)acetylamino]pyridine-4-carboxylic acid (1.1 eq)was combined with 1,2-phenylenediamine (1.0 eq) and heated at 150° C.for 3 hours. The crude product was purified by reversed-phase HPLC(DMSO/5% TFA). LC/MS m/z 279.3 (MH+), R_(t) 1.73 minutes.

Example 2

4-Hydroxy-3-(5-methylbenzimidazol-2-yl)hydropyridino[3,4-b]pyridin-2-one

The title compound was synthesized as described in Example 1 using3-[2-(methoxycarbonyl)acetylamino]-pyridine-4-carboxylic acid and4-methyl-1,2-phenylenediamine. The crude product was purified byreversed-phase HPLC (DMSO/5% TFA). LC/MS m/z 293.3 (MH+), R_(t) 1.99minutes.

Example 3

Ethyl 2-benzimidazol-2-ylacetate

A solution of 1,2-phenylenediamine (1.0 eq) and ethyl3-ethoxy-3-iminopropanoate hydrochloride (1.3 eq) in EtOH was stirred at90° C. overnight. The reaction was cooled to room temperature and thesolvent removed in vacuo. Water and CH₂Cl₂ were added to the residue.The organic layer was separated, dried over Na₂SO₄ and the solventremoved. The solid recovered was used without purification. LC/MS m/z205.2 (MH+), R_(t) 1.44 minutes.

Method A

2-Benzimidazol-2-yl-N-(4-cyano(3-pyridyl))acetamide

LiHMDS (2.5 eq) was added to ethyl 2-benzimidazol-2-ylacetate (1.0 eq)in THF at −78° C. After 1 hour, 3-amino-4-cyanopyridine (0.8 eq) in THFwas added. The resulting mixture was allowed to warm to room temperatureovernight. The mixture was quenched with NH₄Cl (aqueous saturatedsolution) and extracted with EtOAc. The organic layer washed with H₂Oand brine, dried over Na₂SO₄, filtered, and concentrated in vacuo toyield a brown solid. The crude material was purified by silica gelchromatography (5:1 EtOAc:hexane) to yield the desired product. LC/MSm/z 278.3 (MH+), R_(t) 1.88 minutes.

4-Amino-3-benzimidazol-2-ylhydropyridino[3,4-b]pyridin-2-one

2-Benzimidazol-2-yl-N-(4-cyano(3-pyridyl))acetamide (1.0 eq) was heatedin NaOMe (18 eq, 0.5 M in MeOH) at 70° C. for 2 hours. The reactionmixture was cooled, and the resulting solid was filtered and washed withwater to provide the desired product. LC/MS m/z 278.3 (MH+), R_(t) 1.91minutes.

Example 4

Ethyl 2-(5-methylbenzimidazol-2-yl)acetate

The title compound was synthesized as described in Example 3 using4-methyl-1,2-phenylenediamine. LC/MS m/z 219.3 (MH+), R_(t) 1.60minutes.

N-(4-Cyano(3-pyridyl))-2-(5-methylbenzimidazol-2-yl)acetamide

The title compound was synthesized as described in Example 3, Method Ausing ethyl 2-(5-methylbenzimidazol-2-yl)acetate. LC/MS m/z 292.4 (MH+),R_(t) 1.71 minutes.

4-Amino-3-(5-methylbenzimidazol-2-yl)hydropyridino[3,4-b]pyridin-2-one

The title compound was synthesized as described in Example 3, Method Ausing N-(4-cyano(3-pyridyl))-2-(5-methylbenzimidazol-2-yl)acetamide.LC/MS m/z 292.4 (MH+), R_(t) 2.04 minutes.

Example 5

4-(2-Morpholin-4-ylethoxy)-2-nitrophenylamine

Diisopropyl azodicarboxylate (1.1 eq) was added dropwise to a stirredsolution of 4-amino-3-nitrophenol (1.0 eq), triphenylphosphine (1.1 eq),and N-(2-hydroxyethyl)morpholine (1.0 eq), in THF at 0° C. The mixturewas allowed to warm to room temperature and left to stir for 18 hours.The solvent was evaporated and the product was purified by silica gelchromatography (98:2 CH₂Cl₂:MeOH) to yield a dark reddish-brown oil.LC/MS m/z 268.0 (MH+), R_(t) 1.01 minutes.

4-(2-Morpholin-4-ylethoxy)benzene-1,2-diamine

To a solution 4-(2-morpholin-4-ylethoxy)-2-nitrophenylamine (1.0 eq) inEtOH was added Pd/C (0.1 eq). The reaction vessel was repeatedly purgedwith nitrogen, then stirred under a hydrogen atmosphere (1 atm) for 18hours. The product was filtered through a Celite plug, and the plugwashed with EtOH. The diamine was used without purification. LC/MS m/z238.3 (MH+), R_(t) 0.295 minutes.

Ethyl 2-[5-(2-morpholin-4-ylethoxy)benzimidazol-2-yl]acetate

The title compound was synthesized as described in Example 3 using4-(2-morpholin-4-ylethoxy)benzene-1,2-diamine. The organic layer wasconcentrated and the residue purified by silica gel chromatography(10:1:2 CH₂Cl₂:MeOH:EtOAc) to yield a dark reddish brown oil. LC/MS m/z334.4 (MH+), R_(t) 1.08 minutes.

N-(4-Cyano(3-pyridyl))-2-[5-(2-morpholin-4-ylethoxy)benzimidazol-2-yl]acetamide

The title compound was synthesized as described in Example 3, Method Ausing ethyl 2-[5-(2-morpholin-4-ylethoxy)benzimidazol-2-yl]acetate.LC/MS m/z 407.4 (MH+), R_(t) 1.25 minutes.

4-Amino-3-[5-(2-morpholin-4-ylethoxy)benzimidazol-2-yl]hydropyridino[3,4-b]pyridin-2-one

The title compound was synthesized as described in Example 3, Method AusingN-(4-cyano(3-pyridyl))-2-[5-(2-morpholin-4-ylethoxy)benzimidazol-2-yl]acetamide.LC/MS m/z 407.4 (MH+), R_(t) 1.41 minutes.

Example 6

2-[(Ethoxycarbonyl)methyl]benzimidazole-5-carboxylic acid

The title compound was synthesized as described in Example 3 using3,4-diaminobenzoic acid. The crude material was purified by silica gelchromatography (0-5% MeOH/CH₂Cl₂) to afford the desired product as awhite to off-white solid. LC/MS m/z 249.1 (MH+), R_(t) 1.35 minutes.

Ethyl 2-[5-(N,N-dimethylcarbamoyl)benzimidazol-2-yl]acetate

2-[(Ethoxycarbonyl)methyl]benzimidazole-5-carboxylic acid (1.0 eq) wasdissolved in THF. HBTU (1.1 eq) and diisopropylethylamine (2.0 eq) wereadded, followed by dimethylamine (2.0 M in THF, 1.1 eq). The reactionwas stirred at room temperature overnight then concentrated and theresidue was purified by silica gel chromatography (5:95 MeOH/CH₂Cl₂) toafford the desired compound. LC/MS m/z 276.2 (MH+), R_(t) 1.18 minutes.

Method B

[2-(4-Amino-2-oxohydropyridino[3,4-b]pyridin-3-yl)benzimidazol-5-yl]-N,N-dimethylcarboxamide

Ethyl 2-[5-(N,N-dimethylcarbamoyl)benzimidazol-2-yl]acetate (1.0 eq) andanthranilonitrile (1.0 eq) were dissolved in 1,2-dichloroethane, andthen SnCl₄ (5.5 eq) was added. The mixture was heated at refluxovernight. Upon cooling, the mixture was concentrated in vacuo. NaOH (3M) was added to the solid, and the mixture heated at 80° C. for 0.5hours. The solid was filtered and washed sequentially with H₂O, CH₂Cl₂,and acetone. LC/MS indicated that the product was present in the acetonelayer and the solid. These fractions were combined and purified bysilica gel chromatography (5-10% MeOH in CH₂Cl₂ with 1% Et₃N) to givethe desired product. LC/MS m/z 349.3 (MH+), R_(t) 1.68 minutes.

Example 7

5-Fluoro-2-nitrophenylamine

2,4-Difluoronitrobenzene (1.0 eq) was placed in a dry round-bottomedflask equipped with a dry ice condenser charged with acetone/dry ice.Ammonia was condensed into the flask and the resulting solution wasstirred at reflux for 7 hours. A yellow precipitate was formed within 1hour. After 7 hours, the condenser was removed and the liquid ammoniawas allowed to evaporate over several hours. The crude product waspurified by flash chromatography on silica gel (85:15 hexanes:EtOAc,product at R_(f)=0.32, contaminant at R_(f)=0.51). GC/MS m/z 156.1 (M+),R_(t) 11.16 minutes.

5-Morpholin-4-yl-2-nitrophenylamine

5-Fluoro-2-nitrophenylamine (1.0 eq) and morpholine (3.0 eq) weredissolved in NMP and heated at 100° C. for 1 hour. The solution wascooled to room temperature and diluted with water. The resultingprecipitate was filtered and dried under vacuum to yield5-morpholin-4-yl-2-nitrophenylamine. The resulting solid wasrecrystallized from EtOH to afford pure product as a bright yellowsolid. LC/MS m/z 224.1 (MH+), R_(t) 1.89 minutes.

Ethyl 2-(5-morpholin-4-ylbenzimidazol-2-yl)acetate

The title compound was synthesized as described in Example 5 using5-morpholin-4-yl-2-nitrophenylamine. The crude yellow oil was purifiedby flash column chromatography (89.5:10:0.5 CH₂Cl₂:MeOH:Et₃N) to yieldpure product as a yellow solid. LC/MS m/z 290.3 (MH+), R_(t) 1.31minutes.

4-Amino-3-(5-morpholin-4-ylbenzimidazol-2-yl)hydropyridino[3,4-b]pyridin-2-one

The title compound was synthesized as described in Example 6, Method Busing ethyl 2-(5-morpholin-4-ylbenzimidazol-2-yl)acetate. LC/MS m/z363.2 (MH+), R_(t) 1.60 minutes.

Example 8

[1-(3-Amino-4-nitrophenyl)pyrrolidin-3-yl]dimethylamine

The title compound was synthesized as described in Example 7 using3-(dimethylamino)pyrrolidine. LC/MS m/z 251.3 (MH+), R_(t) 1.25 minutes.

Ethyl 2-{5-[3-(dimethylamino)pyrrolidinyl]benzimidazol-2-yl}acetate

The title compound was synthesized as described in Example 5 using[1-(3-amino-4-nitrophenyl)pyrrolidin-3-yl]dimethylamine and theresulting diamine was used according to Example 3 to form thebenzimidazole. The product was obtained as a yellow oil. LC/MS m/z 317.4(MH+), R_(t) 1.36 minutes.

4-Amino-3-{5-[3-(dimethylamino)pyrrolidinyl]benzimidazol-2-yl}hydropyridino[3,4-b]pyridin-2-one

The title compound was synthesized as described in Example 6, Method Busing ethyl 2-[5-(dimethylamino)benzimidazol-2-yl]acetate. LC/MS m/z390.2 (MH+), R_(t) 1.45 minutes.

Example 9

3H-Imidazo[4,5-b]pyridin-2-ylacetonitrile

Ethyl cyanoacetate (1.5 eq) and 2,3-diaminopyridine (1 eq) were heatedat 185° C. for 30 minutes. The reaction mixture was cooled to roomtemperature and the black solid was triturated with ether. The desiredproduct was thus obtained as a dark brown powder. LC/MS m/z 159.1 (MH+),R_(t) 0.44 minutes.

Ethyl 3H-imidazo[4,5-b]pyridin-2-ylacetate

3H-Imidazo[4,5-b]pyridin-2-ylacetonitrile was suspended in EtOH, andgaseous HCl was bubbled through for 3 hours. The suspension initiallydissolved, but a precipitate started forming almost immediately. Thereaction mixture was cooled to 0° C. and a cold saturated NaHCO₃solution was carefully added. Solid NaHCO₃ was also added until a pH of7.6 was achieved. The aqueous phase was then extracted with EtOAc, andthe organic extracts were dried (Na₂SO₄). After evaporation of thesolvent under reduced pressure, the residue was purified bychromatography on silica gel (10% MeOH in CH₂Cl₂ with 1% Et₃N) providingthe desired product as a light brown solid. LC/MS m/z 206.1 (MH+), R_(t)0.97 minutes.

4-Amino-3-(3H-imidazo[4,5-b]pyridin-2-yl)-1,7-naphthyridin-2(1H)-one

LiHMDS (3.0 eq) was added to ethyl 3H-imidazo[4,5-b]pyridin-2-ylacetate(1.0 eq) in THF at −78° C. After 20 minutes, a solution of3-aminopyridine-4-carbonitrile (1.1 eq) in THF was added. The resultingmixture was allowed to warm to room temperature, stirred 3 hours, andthen refluxed overnight. The mixture was cooled to 0° C. and quenchedwith an aqueous saturated NH₄Cl solution. A precipitate formed, wasfiltered off, and was washed repeatedly with ether to yield the desiredcompound as a brown solid. Purification by reverse phase chromatographyafforded the desired product as a yellow solid. LC/MS m/z 279.0 (MH+),R_(t) 1.29 minutes.

Example 10

4-Amino-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1,7-naphthyridin-2(1H)-one

LiHMDS (3.6 eq) was added to ethyl[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]acetate (1.0 eq) and3-aminopyridine-4-carbonitrile (1.0 eq) in THF at 0° C. The reaction wasstirred overnight. The resulting mixture was quenched with an aqueoussaturated NH₄Cl solution and extracted with EtOAc. The combined organiclayers were washed with H₂O and brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo to yield a green solid. The crude material waswashed successively with CH₂Cl₂ and MeOH and then was purified byreverse phase HPLC to provide the desired product. LC/MS m/z 376.3(MH+), R_(t) 1.70 minutes.

Example 11

4-Amino-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-1,6-naphthyridin-2(1H)-one

LiHMDS (3.3 eq) was added to ethyl(5-morpholin-4-yl-1H-benzimidazol-2-yl)acetate (1.0 eq) and4-aminopyridine-3-carbonitrile (see J. Chem. Soc. 1967, p1558-1564; 1.0eq) in THF at 0° C. The reaction was stirred overnight. The resultingmixture was quenched with an aqueous saturated NH₄Cl solution andextracted with EtOAc. The combined organic layers were washed with H₂Oand brine, dried over Na₂SO₄, filtered, and concentrated in vacuo toyield a brown solid. The crude material was washed successively withCH₂Cl₂ and MeOH, and then was purified by reverse phase HPLC to providethe desired product. LC/MS m/z 363.2 (MH+), R_(t) 1.55 minutes.

Example 12

4-Amino-3-{5-[3-(dimethylamino)pyrrolidin-1-yl]-1H-benzimidazol-2-yl}-1,5-naphthyridin-2(1H)-one

LiHMDS (3.6 eq) was added to ethyl{5-[3-(dimethylamino)pyrrolidin-1-yl]-1H-benzimidazol-2-yl}acetate (1.0eq) and 3-aminopyridine-2-carbonitrile (J. Org. Chem. 1958, 1616-1617;1.0 eq) in THF at 0° C. The reaction was stirred overnight and thenheated at 40° C. for 3 hours. The resulting mixture was quenched with anaqueous saturated NH₄Cl solution and extracted with EtOAc. The combinedorganic layers were washed with H₂O and brine, dried over Na₂SO₄,filtered, and concentrated in vacuo to yield a green solid. The crudematerial was washed successively with CH₂Cl₂ and MeOH, and then waspurified by reverse phase HPLC to provide the desired product. LC/MS m/z390.2 (MH+), R_(t) 1.79 minutes.

Example 13

4-Amino-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1,5-naphthyridin-2(1H)-one

LiHMDS (3.6 eq) was added to ethyl[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]acetate (1.0 eq) and3-aminopyridine-2-carbonitrile (1.0 eq) in THF at 0° C. The reaction wasstirred overnight and then heated at 40° C. for 3 hours. The resultingmixture was quenched with an aqueous saturated NH₄Cl solution andextracted with EtOAc. The combined organic layers were washed with H₂Oand brine, dried over Na₂SO₄, filtered, and concentrated in vacuo toyield a green solid. The crude material was washed successively withCH₂Cl₂ and MeOH, and then was purified by reverse phase HPLC to providethe desired product. LC/MS m/z 376.1 (MH+), R_(t) 1.50 minutes.

Example 14

3-(1H-Benzimidazol-2-yl)-4-hydroxy-1,8-naphthyridin-2(1H)-one

The synthesis of the title compound is outlined in Scheme 5.

Example 15

2-(1H-Benzimidazol-2-yl)-N-(4-cyano-1H-pyrazol-5-yl)acetamide

LiHMDS (4.3 eq) was added to ethyl 1H-benzimidazol-2-ylacetate (1.0 eq)5-amino-1H-pyrazole-4-carbonitrile (1.0 eq) in THF at 0° C. After 1hour, the resulting mixture was warmed to room temperature, stirredovernight, and then heated at 40° C. for 4 hours. The mixture wasquenched with an aqueous saturated NH₄Cl solution and extracted withEtOAc. The organic layer was washed with H₂ and brine, dried overNa₂SO₄, filtered, and concentrated in vacuo to yield a tan solid. LC/MSm/z 267.1 (MH+), R_(t) 1.37 minutes.

4-Amino-5-(1H-benzimidazol-2-yl)-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one

2-(1H-Benzimidazol-2-yl)-N-(4-cyano-1H-pyrazol-5-yl)acetamide (1.0 eq)was heated in NaOMe (20 eq, 0.5 M in MeOH) at 100° C. for 2 days. H₂Owas added, and the mixture was extracted with EtOAc. The organic layerwas washed with H₂O and brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo to yield a solid. The material was purified byreverse phase HPLC. LC/MS m/z 267.1 (MH+), R_(t) 1.57 minutes.

Example 16

4-Amino-5-(1H-benzimidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one

LiHMDS (4.3 eq) was added to ethyl 1H-benzimidazol-2-ylacetate (1.1 eq)and 2-aminothiophene-3-carbonitrile (1.0 eq) in THF at 0° C. After 1hour, the resulting mixture was warmed to room temperature and thenstirred overnight. The mixture was quenched with an aqueous saturatedNH₄Cl solution and extracted with EtOAc. The organic layer was washedwith H₂O and brine, dried over Na₂SO₄, filtered, and concentrated invacuo to yield a brown solid. LC/MS m/z 283.1 (MH+), R_(t) 1.88 minutes.

Example 17

7-Amino-6-(1H-benzimidazol-2-yl)-3,4-dihydro-5H-imidazo[4,5-b]pyridin-5-one

LiHMDS (4.4 eq) was added to ethyl 1H-benzimidazol-2-ylacetate (1.0 eq)and 5-amino-1H-imidazole-4-carbonitrile (1.0 eq) in THF at 0° C. After 1hour, the resulting mixture was warmed to room temperature and thenstirred overnight. The mixture was quenched with an aqueous saturatedNH₄Cl solution and extracted with EtOAc. The organic layer was washedwith H₂O and brine, dried over Na₂SO₄, filtered, and concentrated invacuo to yield a brown solid. LC/MS m/z 267.1 (MH+), R_(t) 1.47 minutes.

Example 18

4-Amino-5-(1H-benzimidazol-2-yl)-1-methyl-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one

5-Amino-1-methyl-1H-pyrazole-4-carbonitrile (1.0 eq) and ethyl1H-benzimidazol-2-ylacetate (1.0 eq) were dissolved in THF and driedover sieves. LiHMDS (3 eq) was added dropwise and the mixture stirredfor 18 hours. The mixture was filtered and diluted with EtOAc, thenwashed with an aqueous saturated NH₄Cl solution. The aqueous layer waswashed with EtOAc (3×), and the organic layers combined, dried overMgSO₄, and concentrated yielding pure product. LC/MS m/z 281.0 (MH+),R_(t) 1.41 minutes.

Assay Procedures

In Vitro Kinase Assays for Receptor Tyrosine Kinases

The kinase activity of various protein tyrosine kinases can be measuredby providing ATP and a suitable peptide or protein tyrosine-containingsubstrate, and assaying the transfer of phosphate moiety to the tyrosineresidue. Recombinant proteins corresponding to the cytoplasmic domainsof the flt-1 (VEGFR1), KDR (VEGFR2), and bFGF receptors were expressedin Sf9 insect cells using a Baculovirus expression system (InVitrogen)and purified via Glu antibody interaction (for Glu-epitope taggedconstructs) or by Metal Ion Chromatography (for Hise (SEQ ID NO: 1)tagged constructs). For each assay, test compounds were serially dilutedin DM50 then mixed with an appropriate kinase reaction buffer plus ATP.Kinase protein and an appropriate biotinylated peptide substrate wereadded to give a final volume of 100 μL, reactions were incubated for 1-2hours at room temperature and stopped by the addition of 50 μL of 45 mMEDTA, 50 mM Hepes pH 7.5. Stopped reaction mix (75 μL) was transferredto a streptavidin coated microtiter plate (Boehringer Mannheim) andincubated for 1 hour Phosphorylated peptide product was measured withthe DELFIA time-resolved fluorescence system (Wallac), using aEu-labeled anti-phosphotyrosine antibody PT66 with the modification thatthe DELFIA assay buffer was supplemented with 1 mM MgCl₂ for theantibody dilution. Time resolved fluorescence was read on a Wallac 1232DELFIA fluorometer. The concentration of each compound for 50%inhibition (IC₅₀) was calculated by non-linear regression using XL Fitdata analysis software.

Flt-1, KDR, and bFGFR kinases were assayed in 50 mM Hepes pH 7.0, 2 mMMgCl₂. 10 mM MnCl₂, 1 mM NaF, 1 mM DTT, 1 mg/ml BSA, 2 μM ATP, and 0.42μM biotin-GGGGQDGKDYIVLPI-NH₂. (SEQ ID NO: 2) Flt-1, KDR, and bFGFRkinases were added at 0.1 μg/mL, 0.05 μg/mL, or 0.1 μg/mL respectively.

Each of the following compounds was synthesized and assayed using theprocedures described above:

4-(1-azabicyclo[2.2.2]oct-3-ylamino)-3-(1H-benzimidazol-2-yl)-6-fluoro-1,7-naphthyridin-2(1H)-one;

4-(1-azabicyclo[2.2.2]oct-3-ylamino)-3-(1H-benzimidazol-2-yl)-6-chloro-1,7-naphthyridin-2(1H)-one;

3-benzimidazol-2-yl-4-hydroxyhydropyridino[3,4-b]pyridin-2-one;

4-hydroxy-3-(5-methylbenzimidazol-2-yl)hydropyridino[3,4-b]pyridin-2-one;

4-amino-3-benzimidazol-2-ylhydropyridino[3,4-b]pyridin-2-one;

4-amino-3-(5-methylbenzimidazol-2-yl)hydropyridino[3,4-b]pyridin-2-one;

4-amino-3-[5-(2-morpholin-4-ylethoxy)benzimidazol-2-yl]hydropyridino[3,4-b]pyridin-2-one;

[2-(4-amino-2-oxohydropyridino[3,4-b]pyridin-3-yl)benzimidazol-5-yl]-N,N-dimethylcarboxamide;

4-amino-3-(5-morpholin-4-ylbenzimidazol-2-yl)hydropyridino[3,4-b]pyridin-2-one;

4-amino-3-{5-[3-(dimethylamino)pyrrolidinyl]benzimidazol-2-yl}hydropyridino[3,4-b]pyridin-2-one;

4-amino-3-(3H-imidazo[4,5-b]pyridin-2-yl)-1,7-naphthyridin-2(1H)-one;

4-amino-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1,7-naphthyridin-2(1H)-one;

4-amino-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-1,6-naphthyridin-2(1H)-one;

4-amino-3-{5-[3-(dimethylamino)pyrrolidin-1-yl]-1H-benzimidazol-2-yl}-1,5-naphthyridin-2(1H)-one;

4-amino-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1,5-naphthyridin-2(1H)-one;

3-(1H-benzimidazol-2-yl)-4-hydroxy-1,8-naphthyridin-2(1H)-one;

4-amino-5-(1H-benzimidazol-2-yl)-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one;

4-amino-5-(1H-benzimidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one;

7-amino-6-(1H-benzimidazol-2-yl)-3,4-dihydro-5H-imidazo[4,5-b]pyridin-5-one;and

4-amino-5-(1H-benzimidazol-2-yl)-1-methyl-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one.

Each of the above compounds displayed an IC₅₀ value of less than 10 μMwith respect to VEGFR1, KDR, and bFGF.

It should be understood that the organic compounds according to theinvention may exhibit the phenomenon of tautomerism. As the chemicalstructures within this specification can only represent one of thepossible tautomeric forms, it should be understood that the inventionencompasses any tautomeric form of the drawn structure.

It is understood that the invention is not limited to the embodimentsset forth herein for illustration, but embraces all such forms thereofas come within the scope of the following claims.

2 1 6 PRT Artificial Sequence Description of Artificial Sequence 6X-Histag 1 His His His His His His 1 5 2 15 PRT Artificial SequenceDescription of Artificial Sequence Synthetic peptide 2 Gly Gly Gly GlyGln Asp Gly Lys Asp Tyr Ile Val Leu Pro Ile 1 5 10 15

What is claimed is:
 1. A compound having the structure I, a tautomer ofthe compound, a pharmaceutically acceptable salt of the compound, or apharmaceutically acceptable salt of the tautomer

wherein, Y is selected from the group consisting of —OH, —OR⁸ groups,—SH, —SR⁹ groups, —NR¹⁰R¹¹ groups, —CN, —C(═O)—R¹² groups, substitutedand unsubstituted alkyl groups, substituted and unsubstituted alkenylgroups, substituted and unsubstituted alkynyl groups, substituted andunsubstituted aralkyl groups, substituted and unsubstitutedheterocyclylalkyl groups, substituted and unsubstituted alkylaminoalkylgroups, substituted and unsubstituted dialkylaminoalkyl groups,substituted and unsubstituted arylaminoalkyl groups, substituted andunsubstituted diarylaminoalkyl groups, substituted and unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted and unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(alkyl)(heterocyclyl)aminoalkyl groups, substituted and unsubstituted(aryl)(heterocyclyl)aminoalkyl groups, substituted and unsubstitutedheterocyclyl groups, substituted and unsubstituted aryl groups,substituted and unsubstituted hydroxyalkyl groups, substituted andunsubstituted alkoxyalkyl groups, substituted and unsubstitutedaryloxyalkyl groups, and substituted and unsubstitutedheterocyclyloxyalkyl groups; Z is selected from the group consisting ofO, S, and NR¹³ groups; R¹ and R² join to form a 5 membered substitutedor unsubstituted ring comprising at least one O, N, or S atom; R³ andR¹³ may be the same or different and are selected from the groupconsisting of H, —OH, substituted and unsubstituted alkoxy groups,substituted and unsubstituted alkyl groups, substituted andunsubstituted aryl groups, —C(═O)H, —C(═O)-alkyl groups, and —C(═O)-arylgroups; R⁴, R⁵, R⁶, and R⁷ may be the same or different and areindependently selected from the group consisting of H, Cl, Br, F, I,—NO₂, —CN, —OH, —OR¹⁴ groups, —NR¹⁵R¹⁶ groups, —C(═O)R¹⁷ groups, —SH,—SR¹⁸ groups, —S(═O)R¹⁹ groups, S(═O)₂R²⁰ groups, substituted andunsubstituted amidinyl groups, substituted and unsubstituted guanidinylgroups, substituted and unsubstituted primary, secondary, and tertiaryalkyl groups, substituted and unsubstituted aryl groups, substituted andunsubstituted alkenyl groups, substituted and unsubstituted alkynylgroups, substituted and unsubstituted heterocyclyl groups, substitutedand unsubstituted alkylaminoalkyl groups, substituted and unsubstituteddialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkylgroups, substituted and unsubstituted diarylaminoalkyl groups,substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups,substituted and unsubstituted heterocyclylalkyl groups, substituted andunsubstituted aminoalkyl groups, substituted and unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(alkyl)(heterocyclyl)aminoalkyl groups, substituted and unsubstituted(aryl)(heterocyclyl)aminoalkyl groups, substituted and unsubstitutedhydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups,substituted and unsubstituted aryloxyalkyl groups, and substituted andunsubstituted heterocyclyloxyalkyl groups; R⁸ is selected from the groupconsisting of substituted and unsubstituted alkyl groups, substitutedand unsubstituted aryl groups, substituted and unsubstitutedheterocyclyl groups, substituted and unsubstituted heterocyclylalkylgroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkylgroups, —C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,—C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —NH₂, —NH(alkyl) groups, —NH(aryl) groups,—N(alkyl)₂ groups, —N(alkyl)(aryl) groups, —N(aryl)₂ groups,—C(═O)NH(heterocyclyl) groups, —C(═O)N(heterocyclyl)₂ groups,—C(═O)N(alkyl)(heterocyclyl) groups, and —C(═O)N(aryl)(heterocyclyl)groups; R⁹ and R¹⁸ may be the same or different and are independentlyselected from the group consisting of substituted and unsubstitutedalkyl groups, and substituted and unsubstituted aryl groups; R¹⁰ isselected from the group consisting of H, substituted and unsubstitutedalkyl groups, substituted and unsubstituted aryl groups, and substitutedand unsubstituted heterocyclyl groups; R¹¹ is selected from the groupconsisting of H, substituted and unsubstituted alkyl groups, substitutedand unsubstituted aryl groups, substituted and unsubstitutedheterocyclyl groups, —OH, alkoxy groups, aryloxy groups, —NH₂,substituted and unsubstituted heterocyclylalkyl groups, substituted andunsubstituted aminoalkyl groups, substituted and unsubstitutedalkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkylgroups, substituted and unsubstituted arylaminoalkyl groups, substitutedand unsubstituted diarylaminoalkyl groups, substituted and unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted alkylaminogroups, substituted and unsubstituted arylamino groups, substituted andunsubstituted dialkylamino groups, substituted and unsubstituteddiarylamino groups, substituted and unsubstituted (alkyl)(aryl)aminogroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkylgroups, —C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,—C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —C(═O)-heterocyclyl groups,—C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,—C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups,—C(═O)—N(aryl)(heterocyclyl) groups, substituted and unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(alkyl)(heterocyclyl)aminoalkyl groups, substituted and unsubstituted(aryl)(heterocyclyl)aminoalkyl groups, substituted and unsubstitutedhydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups,substituted and unsubstituted aryloxyalkyl groups, and substituted andunsubstituted heterocyclyloxyalkyl groups; R¹² is selected from thegroup consisting of H, —OH, alkoxy groups, aryloxy groups, —NH₂,—NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂ groups, —N(aryl)₂groups, —N(alkyl)(aryl) groups, substituted and unsubstituted alkylgroups, substituted and unsubstituted aryl groups, —NH(heterocyclyl)groups, —N(heterocyclyl)₂ groups, —N(alkyl)(heterocyclyl) groups, and—N(aryl)(heterocyclyl) groups; R¹⁴ is selected from the group consistingof substituted and unsubstituted alkyl groups, substituted andunsubstituted aryl groups, substituted and unsubstituted heterocyclylgroups, substituted and unsubstituted heterocyclylalkyl groups, —C(═O)H,—C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)-heterocyclyl groups,—C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups,—C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl)groups, —C(═O)NH-heterocyclyl groups, —C(═O)N-(heterocyclyl)₂ groups,—C(═O)N(alkyl)(heterocyclyl) groups, —C(═O)N(aryl)(heterocyclyl) groups,substituted and unsubstituted aminoalkyl groups, substituted andunsubstituted alkylaminoalkyl groups, substituted and unsubstituteddialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkylgroups, substituted and unsubstituted diarylaminoalkyl groups,substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups,substituted and unsubstituted heterocyclylaminoalkyl groups, substitutedand unsubstituted diheterocyclylaminoalkyl groups, substituted andunsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted andunsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted andunsubstituted alkoxyalkyl groups, substituted and unsubstitutedaryloxyalkyl groups, substituted and unsubstituted hydroxyalkyl groups,and substituted and unsubstituted heterocyclyloxyalkyl groups; R¹⁵ isselected from the group consisting of H, substituted and unsubstitutedalkyl groups, substituted and unsubstituted aryl groups, and substitutedand unsubstituted heterocyclyl groups; R¹⁶ is selected from the groupconsisting of H, substituted and unsubstituted alkyl groups, substitutedand unsubstituted aryl groups, substituted and unsubstitutedheterocyclyl groups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups,—C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups,—C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl)groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups, substituted andunsubstituted aminoalkyl groups, substituted and unsubstitutedalkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkylgroups, substituted and unsubstituted arylaminoalkyl groups, substitutedand unsubstituted diarylaminoalkyl groups, substituted and unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted and unsubstitutedheterocyclylalkyl groups, —C(═O)-heterocyclyl groups,—C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,—C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups,—C(═O)—N(aryl)(heterocyclyl) groups, substituted and unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(heterocyclyl)(alkyl)aminoalkyl groups, substituted and unsubstituted(heterocyclyl)(aryl)aminoalkyl groups, substituted and unsubstitutedhydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups,substituted and unsubstituted aryloxyalkyl groups, and substituted andunsubstituted heterocyclyloxyalkyl groups; and R¹⁷, R¹⁹, and R²⁰ may bethe same or different and are independently selected from the groupconsisting of H, —NH₂, —NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂groups, —N(aryl)₂ groups, —N(alkyl)(aryl) groups, —NH(heterocyclyl)groups, —N(heterocyclyl)(alkyl) groups, —N(heterocyclyl)(aryl) groups,—N(heterocyclyl)₂ groups, substituted and unsubstituted alkyl groups,substituted and unsubstituted aryl groups, —OH, substituted andunsubstituted alkoxy groups, substituted and unsubstituted heterocyclylgroups, substituted and unsubstituted aryloxy groups, heterocyclyloxygroups, —NHOH, —N(alkyl)OH groups, —N(aryl)OH groups, —N(alkyl)O-alkylgroups, —N(aryl)O-alkyl groups, —N(alkyl)O-aryl groups, and—N(aryl)O-aryl groups.
 2. The compound according to claim 1, wherein Yis selected from the group consisting of —OH, —OR⁸ groups, and —NR¹⁰R¹¹groups.
 3. The compound according to claim 1, wherein Y is a —NR¹⁰R¹¹group.
 4. The compound according to claim 1, wherein Z is an NR¹³ group.5. The compound according claim 1, wherein R⁴ and R⁷ are hydrogen and R⁵and R⁶ are selected from the group consisting of hydrogen and alkylgroups having from 1 to 4 carbon atoms.
 6. The compound according toclaim 1, wherein R⁵ or R⁶ is an —OR¹⁴ group and R¹⁴ is an alkyl, aryl,heterocyclyl, or heterocyclylalkyl group.
 7. The compound according toclaim 1, wherein R⁵ or R⁶ is a —OCH₂(CH₂)_(q)(heterocyclyl) group and qis 0, 1, 2, 3, or
 4. 8. The compound according to claim 1, wherein R¹⁷is selected from the group consisting of substituted and unsubstitutedalkyl groups, substituted and unsubstituted aryl groups, —NH₂,—NH(alkyl) groups, —N(alkyl)₂ groups, —NH(aryl) groups, —N(aryl)₂groups, —N(alkyl)(aryl) groups, —NH(heterocyclyl) groups,—N(heterocyclyl)(alkyl) groups, —N(heterocyclyl)(aryl) groups,—N(heterocyclyl)₂ groups, and N-containing heterocycles, wherein theN-containing heterocycles are bonded to the carbonyl carbon of the—C(═O)—R¹⁷ group through either a nitrogen atom or a carbon atom in therings of the N-containing heterocycles.
 9. The compound according toclaim 1, wherein one of R¹⁰ or R¹¹ is H.
 10. The compound according toclaim 1, wherein R¹⁰ and R¹¹ are both H.
 11. The compound according toclaim 1, wherein R¹ and R² join to form a substituted or unsubstituted 5membered ring comprising at least one N atom.
 12. The compound accordingto claim 1, wherein R¹ and R² join to form a substituted orunsubstituted 5 membered ring comprising one S atom.
 13. The compoundaccording to claim 1, wherein at least one of R⁵ or R⁶ is a substitutedor unsubstituted heterocyclyl group.
 14. The compound according to claim1, wherein at least one of R⁵ or R⁶ is a substituted or unsubstitutedheterocyclyl group comprising at least one O or N atom.
 15. The compoundaccording to claim 1, wherein at least one of R⁵ or R⁶ is a substitutedor unsubstituted heterocyclyl group selected from the group consistingof morpholine, piperazine, piperidine, 1,2,3-triazole, 1,2,4-triazole,tetrazole, pyrrolidine, pyrazole, pyrrole, thiomorpholine,homopiperazine, benzimidazole, oxazolidin-2-one, pyrrolidin-2-one,imidazole, isoxazole, oxazole, isothiazole, thiazole, thiophene, furan,pyran, tetrahydrothiophene, tetrahydrofuran, tetrahydropyran, andpyridine.
 16. The compound according to claim 1, wherein Y is selectedfrom the group consisting of from —N(CH₃)₂, —NH(CH₃), —NH(CH₂CH₃),—N(CH₂CH₃)₂, —NH(aryl) groups, —N(aryl)₂ groups, —NHNH₂, —NHN(CH₃)₂,—N(CH₃)NH(CH₃), —NH(CH₂)_(m)NH₂ groups, —NH(CH₂)_(m)NH(alkyl) groups,—NH(CH₂)_(m)N(alkyl)₂ groups, —N(alkyl)(CH₂)_(m)NH₂ groups,—N(alkyl)(CH₂)_(m)NH(alkyl) groups, —N(alkyl)(CH₂)_(m)N(alkyl)₂ groups,—NH(CH₂)_(n)(heterocyclyl) groups, —N(alkyl)[(CH₂)_(n)(heterocyclyl)]groups, —NH(CH₂)_(m)OH groups, —NH(CH₂)_(m)OCH₃ groups,—NHCH₂CH(NH₂)CH(CH₃)₂, —NH(2-aminocyclohexyl), —NH(cyclohexyl), —NHOCH₃,—NH(N-morpholinyl), and —NH(quinuclidyl), wherein m is 2, 3, or 4 and nis 0, 1, 2, or
 3. 17. The compound according to claim 1, wherein thecompound having the structure I has the structure IA

wherein R²¹ is selected from H or substituted or unsubstituted alkylgroups; R²² may be the same or different from R⁴, R⁵, R⁶, R⁷ and isindependently selected from H, Cl, Br, F, I, —NO₂, —CN, —OH, —OR¹⁴groups, —NR¹⁵R¹⁶ groups, —C(═O)R¹⁷ groups, —SH, —SR¹⁸ groups, —S(═O)R¹⁹groups, S(═O)₂R²⁰ groups, substituted or unsubstituted amidinyl groups,substituted or unsubstituted guanidinyl groups, substituted orunsubstituted primary, secondary, or tertiary alkyl groups, substitutedor unsubstituted aryl groups, substituted or unsubstituted alkenylgroups, substituted or unsubstituted alkynyl groups, substituted orunsubstituted heterocyclyl groups, substituted or unsubstitutedalkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkylgroups, substituted or unsubstituted arylaminoalkyl groups, substitutedor unsubstituted diarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstitutedheterocyclylalkyl groups, substituted or unsubstituted aminoalkylgroups, substituted or unsubstituted heterocyclylaminoalkyl groups,substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups; and R³ through R²⁰, Y, and Z have thevalues set forth in claim
 1. 18. The compound according to claim 1,wherein the compound having the structure I has the structure IB

wherein R²¹ is selected from H or substituted or unsubstituted alkylgroups; R²² may be the same or different from R⁴, R⁵, R⁶, R⁷ and isindependently selected from H, Cl, Br, F, I, —NO₂, —CN, —OH, —OR¹⁴groups, —NR¹⁵R¹⁶ groups, —C(═O)R¹⁷ groups, —SH, —SR¹⁸ groups, —S(═O)R¹⁹groups, S(═O)₂R²⁰ groups, substituted or unsubstituted amidinyl groups,substituted or unsubstituted guanidinyl groups, substituted orunsubstituted primary, secondary, or tertiary alkyl groups, substitutedor unsubstituted aryl groups, substituted or unsubstituted alkenylgroups, substituted or unsubstituted alkynyl groups, substituted orunsubstituted heterocyclyl groups, substituted or unsubstitutedalkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkylgroups, substituted or unsubstituted arylaminoalkyl groups, substitutedor unsubstituted diarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstitutedheterocyclylalkyl groups, substituted or unsubstituted aminoalkylgroups, substituted or unsubstituted heterocyclylaminoalkyl groups,substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups; and R³ through R²⁰, Y, and Z have thevalues set forth in claim
 1. 19. The compound according to claim 1,wherein the compound having the structure I has the structure IC

wherein R²¹ and R²² may be the same or different from R⁴, R⁵, R⁶, R⁷ andeach other and are independently selected from H, Cl, Br, F, I, —NO₂,—CN, —OH, —OR¹⁴ groups, —NR¹⁵R¹⁶ groups, —C(═O)R¹⁷ groups, —SH, —SR¹⁸groups, —S(═O)R¹⁹ groups, S(═O)₂R₂₀ groups, substituted or unsubstitutedamidinyl groups, substituted or unsubstituted guanidinyl groups,substituted or unsubstituted primary, secondary, or tertiary alkylgroups, substituted or unsubstituted aryl groups, substituted orunsubstituted alkenyl groups, substituted or unsubstituted alkynylgroups, substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted alkylaminoalkyl groups, substituted or unsubstituteddialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkylgroups, substituted or unsubstituted diarylaminoalkyl groups,substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substitutedor unsubstituted heterocyclylalkyl groups, substituted or unsubstitutedaminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkylgroups, substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups; and R³ through R²⁰, Y, and Z have thevalues set forth in claim
 1. 20. A pharmaceutical formulation,comprising the compound according to claim 1 in combination with apharmaceutically acceptable carrier.
 21. A method of treating a patientin need of an inhibitor of vascular endothelial growth factor receptortyrosine kinase, comprising administering an effective amount of thepharmaceutical formulation according to claim 20 to a patient in needthereof.